Differences in treatment response between female and male psoriatic arthritis patients during IL-12/23 therapy with or without methotrexate: post hoc analysis of results from the randomised MUST trial.

BACKGROUND: The influence of sex on treatment outcomes during interleukin-12/23 therapy in patients with psoriatic arthritis (PsA) has not been explored. OBJECTIVE: To conduct exploratory post hoc analyses of sex-stratified data from the MUST trial, an investigator-initiated, multicentre, phase 3b study in which patients with active PsA initiating treatment with open-label ustekinumab were randomised to treatment with placebo or methotrexate (MTX). METHODS: We evaluated baseline characteristics, key treatment outcomes and adverse events stratified by sex, with a focus on outcomes that did not include erythrocyte sedimentation rate (ESR) as a component due to the known elevation of ESR in females. RESULTS: A total of 166 patients were treated with ustekinumab+MTX (37 female, 50 male) or ustekinumab+placebo (32 female, 47 male). At baseline, females had a significantly longer time since PsA diagnosis and greater impairment in physical function, but similar joint counts. At week 24, both females and males showed marked improvements to ustekinumab with or without MTX. Females generally had numerically reduced treatment responses compared with males, although differences did not achieve statistical significance. MTX did not show an overall effect on treatment outcomes, but was associated with faster enthesitis responses in males only. Adverse events were generally comparable, but females in the ustekinumab+MTX group had higher levels of gastrointestinal disorders. CONCLUSION: Females and males with PsA had differences in baseline characteristics, treatment responses and adverse events during therapy. A better understanding of sex-based differences in PsA may help optimise treatment.

Psoriasis and Psoriatic Arthritis Have a Major Impact on Quality of Life and Depressive Symptoms: A Cross-Sectional Study of 300 Patients.

INTRODUCTION: Psoriasis (Pso) and psoriatic arthritis (PsA) can reduce the quality of life (QoL) and are known to be associated with depression. Within this study, we aimed to assess the burden of disease, functional capacity, quality of life, and depressive symptoms and identify factors predicting functional impairment and depression in patients with psoriatic disease. METHODS: A cross-sectional survey was conducted in a cohort of 300 patients with psoriatic disease including 150 patients from a university hospital dermatology outpatient clinic and 150 patients from a university hospital rheumatology outpatient clinic. Questionnaire-based assessment of signs of arthritis (Psoriasis Epidemiology Screening Tool; PEST), functional status (Functional Questionnaire Hannover; FFbH), quality of life (World Health Organization Quality of Life Brief Version; WHOQOL-BREF), and depressive symptoms (Patient health questionnaire 9; PHQ-9) and retrospective medical chart analysis were performed. RESULTS: Despite treatment, burden of disease was high. Joint pain was reported in multiple regions in patients with Pso (n = 111) and patients with PsA (n = 189), but with differences in frequency and distribution patterns of symptoms. Functional impairment in everyday life was independently associated with diagnosis of PsA (odds ratio [OR] 9.56, p = 0.005), depressive symptoms (OR 5.44, p < 0.001) and age (OR 1.04, p = 0.033). At least mild depressive symptoms were demonstrated in 54% and 69% of patients with Pso and PsA, respectively. In a logistic regression model, depressive symptoms were independently associated with functional impairment (OR 4.50, p = 0.003), axial complaints (OR 2.80, p = 0.030), diagnosis of psoriatic arthritis (OR 2.69, p = 0.046), and number of joint regions with complaints (OR 1.10, p = 0.032). CONCLUSION: Functional impairment, QoL, and depressive symptoms are mutually interdependent. Early diagnosis of PsA and initiation of anti-inflammatory therapy are essential to avoid long-term damage, disability, and mental health complications. However, despite therapy many patients with PsA, and especially female patients, report a substantial residual disease burden due to their psoriatic disease which will need to be addressed by a more patient-centered approach.

Sleep behaviour differs in women and men with psoriatic arthritis and axial spondyloarthritis with impact on quality of life and depressive symptoms.

OBJECTIVES: Axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) may have a profound impact on sleep and health-related quality of life. The aim of this study was to assess sleep quality and quality of life and determine associated factors in patients treated with spondyloarthritides (SpA). METHODS: Cross-sectional questionnaire-based assessment of sleep behaviour, quality of life, functional impairment and depression (Regensburg Insomnia Scale, WHO Quality of Life questionnaire, Funktionsfragebogen Hannover questionnaire, Beck Depression Inventory II, Patient health questionnaire 9) and retrospective medical chart analysis of a monocentric cohort of 330 patients with SpA (n=168 PsA and n=162 axSpA). RESULTS: 46.6% of patients with SpA demonstrated abnormal sleep behaviour. Linear regression models showed HLA-B27 positivity, Bath Ankylosing Spondylitis Disease Activity Index, depressive symptoms, functional capacity and disease duration to be predictive of insomnia symptoms in axSpA, respectively, depressive symptoms, female sex and Disease Activity Score 28 in patients with PsA. Patients with unrestful sleep had a significantly reduced health-related quality of life (p<0.001) as well as significantly more depressive symptoms (p<0.001). Satisfaction with health was rated significantly lower (p<0.001), indicating poor sleep as a burden on general well-being.In particular, female patients had a significantly worse sleep quality with a prolonged sleep latency (p=0.009), increased sleep disturbances (p=0.014) and unrestful sleep (p<0.001) as well as a reduced physical and mental health-related quality of life (p=0.015, p<0.001) and more depressive symptoms (p=0.015). CONCLUSION: Despite treatment, many patients with SpA demonstrate abnormal sleep behaviour with symptoms of insomnia and a reduced quality of life with significant differences between male and female patients. An interdisciplinary and holistic approach may be needed to address unmet needs.

Favourable outcome of acute hepatitis E infection in patients with ANCA-associated vasculitis.

BACKGROUND: Hepatitis E virus (HEV) infection is a frequent cause of acute viral hepatitis. Immunocompromised patients are at increased risk for viral infection and chronic courses of hepatitis. Whether patients with autoimmune diseases are at risk of developing clinically relevant hepatitis or even chronic liver disease after HEV infection is discussed controversially. ANCA-associated vasculitis is a rare autoimmune disease with potentially life-threatening organ involvement, thus requiring intensive immunosuppression with glucocorticoids, cyclophosphamide, or rituximab. As there are no reports available on the infection with HEV in patients with ANCA-associated vasculitis, clinical decision making in such cases is based on experiences from other disease entities. Therefore, in this study we analyzed the course of liver disease and the therapeutic management of autoimmune vasculitis in a retrospective cohort of five patients with ANCA-associated vasculitis and acute hepatitis E. RESULTS: Four patients were on immunosuppressive maintenance therapy and one patient was on remission induction therapy with cyclophosphamide and high dose glucocorticoids. All patients had at least one potentially hepatotoxic co-medication at the time of hepatitis. Hepatitis-associated clinical symptoms were recorded in four of five patients. The course of hepatitis was characterized by strongly elevated transaminases, a temporary liver failure was observed in one case. The management of hepatitis E included cessation of the immunosuppressants in all patients, whereas oral glucocorticoids were not discontinued. Under this regime, all patients cleared the virus without additional anti-viral treatment. Liver enzymes normalized one month after they peaked. In the follow-up period of at least 1.5 years (range 1.5-12 years), no chronic liver disease was observed, although one patient died of cholangiocarcinoma with liver metastases some years after HEV infection. Vasculitis was not active in our patient cohort at the time of HEV infection. However, inflammatory flares occured in three of five patients after discontinuation of the immunosuppressive therapy. Immunosuppressants were paused for a median time of 4 weeks and after their resumption vasculitic disease activity was controlled in all patients. CONCLUSIONS: Acute HEV infection in patients with ANCA-associated vasculitis shows a favorable outcome of liver disease but bears the risk of inflammatory flares due to cessation of immunosuppression.

A Barcoded Flow Cytometric Assay to Explore the Antibody Responses Against SARS-CoV-2 Spike and Its Variants.

The SARS-CoV-2 pandemic has spread to all parts of the world and can cause life-threatening pneumonia and other severe disease manifestations known as COVID-19. This health crisis has resulted in a significant effort to stop the spread of this new coronavirus. However, while propagating itself in the human population, the virus accumulates mutations and generates new variants with increased fitness and the ability to escape the human immune response. Here we describe a color-based barcoded spike flow cytometric assay (BSFA) that is particularly useful to evaluate and directly compare the humoral immune response directed against either wild type (WT) or mutant spike (S) proteins or the receptor-binding domains (RBD) of SARS-CoV-2. This assay employs the human B lymphoma cell line Ramos, transfected for stable expression of WT or mutant S proteins or a chimeric RBD-CD8 fusion protein. We find that the alpha and beta mutants are more stably expressed than the WT S protein on the Ramos B cell surface and/or bind with higher affinity to the viral entry receptor ACE2. However, we find a reduce expression of the chimeric RBD-CD8 carrying the point mutation N501Y and E484K characteristic for the alpha and beta variant, respectively. The comparison of the humoral immune response of 12 vaccinated probands with 12 COVID-19 patients shows that after the boost, the S-specific IgG class immune response in the vaccinated group is similar to that of the patient group. However, in comparison to WT the specific IgG serum antibodies bind less well to the alpha variant and only poorly to the beta variant S protein. This is in line with the notion that the beta variant is an immune escape variant of SARS-CoV-2. The IgA class immune response was more variable than the IgG response and higher in the COVID-19 patients than in the vaccinated group. In summary, we think that our BSFA represents a useful tool to evaluate the humoral immunity against emerging variants of SARS-CoV-2 and to analyze new vaccination protocols against these variants.

Cell Survival Failure in Effector T Cells From Patients With Systemic Lupus Erythematosus Following Insufficient Up-Regulation of Cold-Shock Y-Box Binding Protein 1.

OBJECTIVE: The importance of cold-shock Y-box binding protein 1 (YB-1) for cell homeostasis is well-documented based on prior observations of its association with certain cancer entities. This study was undertaken to explore the role of YB-1 in T cell homeostasis and survival and the potential contribution of YB-1 to the pathogenesis of systemic lupus erythematosus (SLE). METHODS: In the peripheral blood from 25 SLE patients and 25 healthy donors, the expression of YB-1 and frequency of T cell apoptosis was analyzed by quantitative polymerase chain reaction (qPCR) and fluorescence-activated cell sorting of CD4+ T cells ex vivo and also analyzed in T cells in vitro after 6 days of stimulation with anti-CD3-coupled or anti-CD3/anti-CD28-coupled microspheres. YB-1 was overexpressed using lentiviral transduction with wild-type green fluorescent protein (wtGFP) YB-1, and knockdown of YB-1 was achieved using specific short hairpin RNA (shRNA) (3-fold reduction; P < 0.0001). RESULTS: YB-1 expression was significantly lower in apoptosis-prone T cells and in activated T cells from SLE patients compared to YB-1 expression in nonapoptotic T cells and activated T cells from healthy donors (P = 0.001). Knockdown of YB-1 in T cells consequently led to expression of proapoptotic molecules and caspase 3 activation (1.6-fold), and subsequently, to apoptosis. Furthermore, YB-1 promoted survival pathways involving enhanced protein expression of the kinase Akt (2-fold) and Bcl-2 (3-fold), even when Fas/CD95 was triggered. YB-1-mediated T cell survival was reversed by Akt and phosphatidylinositol 3-kinase (PI3K) inactivation. In SLE patients, rescue of YB-1 expression strongly promoted survival of T cells and even prevented cell death in T cells that were extremely apoptosis-prone. CONCLUSION: Our data show that failure of YB-1 up-regulation in T cells from SLE patients led to enhanced apoptosis. These findings imply that YB-1 plays a crucial role in the disturbed homeostasis of activated T cells leading to hematopoietic alterations in SLE. These insights may help facilitate the development of new treatment strategies for SLE.

Comparison of the effects of tocilizumab monotherapy and adalimumab in combination with methotrexate on bone erosion repair in rheumatoid arthritis.

OBJECTIVE: To compare the effects of interleukin-6 (IL-6) receptor and tumour necrosis factor inhibition on inducing repair of existing bone erosions in patients with very early rheumatoid arthritis (RA). METHODS: Prospective non-randomised observational study in patients with active erosive RA with inadequate response to methotrexate (MTX) receiving either tocilizumab (TOC) monotherapy or adalimumab (ADA) with MTX for 52 weeks. Erosion volumes were assessed in metacarpal heads (MCH) and the radius by high-resolution peripheral quantitative CT at baseline and after 52 weeks. Clinical response was monitored using Clinical Disease Activity Index, Simple Disease Activity Index and Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) scores every 12 weeks. RESULTS: TOC (N=33) and ADA/MTX (N=33) treatment groups were balanced for age, sex, body mass index, comorbidities, disease and activity, functional state, autoantibody status, baseline bone damage and baseline bone biomarkers. Both TOC (DAS28-ESR: baseline: 6.2±0.5; 52 weeks: 2.3±1.0) and ADA/MTX (6.3±0.6; 2.8±1.2) significantly reduced disease activity. Erosion volumes significantly decreased in the MCH and radius of patients with RA treated with TOC (p<0.001) but not in patients treated with ADA/MTX (p=0.77), where they remained stable in size. Mean decrease in erosion volume in TOC-treated patients was -1.0±1.1 mm3 and -3.3±5.9 mm3 in the MCH and radius of TOC-treated patients, respectively, and -0.05±0.9 mm3 and -0.08±4.1 mm3 in patients treated with ADA/MTX. CONCLUSIONS: The REBONE study shows that TOC monotherapy achieves more pronounced repair of existing bone erosions than ADA/MTX. Hence, IL-6 is a central factor for the disturbed bone homeostasis in the joints of patients with RA.

Effects of ustekinumab versus tumor necrosis factor inhibition on enthesitis: Results from the enthesial clearance in psoriatic arthritis (ECLIPSA) study.

OBJECTIVES: To date, all studies addressing on anti-inflammatory drugs in PsA have been carried out in psoriatic arthritis (PsA) patients with polyarticular disease. Specific studies on enthesitis are missing. IL-23 is considered to play a central role in the development of enthesitis. We therefore speculated that therapeutic inhibition of IL-12/IL-23 is particularly effective in enthesitis-driven PsA patients. METHODS: Enthesial CLearance In PSoriatic Arthritis (ECLIPSA) is a prospective randomized-controlled open-label study. Patients with PsA with active enthesitis were randomized 1:1 to receive either ustekinumab (UST; arm 1) or tumor necrosis factor inhibitors (TNFi; arm 2). Primary endpoint was complete clearance of enthesitis, defined by Spondyloarthritis Research Consortium of Canada (SPARCC) index equal to zero at 24 weeks. RESULTS: 51 patients (UST = 25; TNFi = 26) were screened, 47 enrolled (UST = 23; TNFi = 24) and 46 completed the study. Mean ±â€¯SD SPARCC index at baseline was 4.8 ±â€¯2.6 in the UST group and 3.5 ±â€¯2.3 in the TNFi group with no significant difference. After 24 weeks, 73.9% of UST patients and 41.7% of TNFi patients reached the primary endpoint (SPARCC = 0) indicating clearance from enthesitis (p = 0.018). UST achieved superior responses as compared to TNFi with respect to enthesitis (p = 0.007) and psoriatic skin disease (p = 0.030) but not for arthritis (p = 0.95). CONCLUSION: These results indicate that p40-IL-12/IL-23 inhibition is superior to TNFi in the clearance of enthesitis. Future stratified therapeutic approaches in PsA patients may therefore consider the presence or absence of enthesitis as a discriminator of response between different cytokine blocking modalities.

Antimodified protein antibody response pattern influences the risk for disease relapse in patients with rheumatoid arthritis tapering disease modifying antirheumatic drugs.

OBJECTIVE: To perform a detailed analysis of the autoantibody response against post-translationally modified proteins in patients with rheumatoid arthritis (RA) in sustained remission and to explore whether its composition influences the risk for disease relapse when tapering disease modifying antirheumatic drug (DMARD) therapy. METHODS: Immune responses against 10 citrullinated, homocitrullinated/carbamylated and acetylated peptides, as well as unmodified vimentin (control) and cyclic citrullinated peptide 2 (CCP2) were tested in baseline serum samples from 94 patients of the RETRO study. Patients were classified according to the number of autoantibody reactivities (0-1/10, 2-5/10 and >5/10) or specificity groups (citrullination, carbamylation and acetylation; 0-3) and tested for their risk to develop relapses after DMARD tapering. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining the role of autoantibodies in predicting relapse. RESULTS: Patients varied in their antimodified protein antibody response with the extremes from recognition of no (0/10) to all antigens (10/10). Antibodies against citrullinated vimentin (51%), acetylated ornithine (46%) and acetylated lysine (37%) were the most frequently observed subspecificities. Relapse risk significantly (p=0.011) increased from 18% (0-1/10 reactivities) to 34% (2-5/10) and 55% (>5/10). With respect to specificity groups (0-3), relapse risk significantly (p=0.021) increased from 18% (no reactivity) to 28%, 36% and finally to 52% with one, two or three antibody specificity groups, respectively. CONCLUSIONS: The data suggest that the pattern of antimodified protein antibody response determines the risk of disease relapse in patients with RA tapering DMARD therapy. TRIAL REGISTRATION NUMBER: 2009-015740-42; Results.

Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts.

Inflammation has important roles in tissue regeneration, autoimmunity, and cancer. Different inflammatory stimuli can lead to bone loss by mechanisms that are not well understood. We show that skin inflammation induces bone loss in mice and humans. In psoriasis, one of the prototypic IL-17A-mediated inflammatory human skin diseases, low bone formation and bone loss correlated with increased serum IL-17A levels. Similarly, in two mouse models with chronic IL-17A-mediated skin inflammation,K14-IL17A(ind)andJunB(Δep), strong inhibition of bone formation was observed, different from classical inflammatory bone loss where osteoclast activation leads to bone degradation. We show that under inflammatory conditions, skin-resident cells such as keratinocytes, γδ T cells, and innate lymphoid cells were able to express IL-17A, which acted systemically to inhibit osteoblast and osteocyte function by a mechanism involving Wnt signaling. IL-17A led to decreased Wnt signaling in vitro, and importantly, pharmacological blockade of IL-17A rescued Wnt target gene expression and bone formation in vivo. These data provide a mechanism where IL-17A affects bone formation by regulating Wnt signaling in osteoblasts and osteocytes. This study suggests that using IL-17A blocking agents in psoriasis could be beneficial against bone loss in these patients.

Quantitative and Qualitative Changes of Bone in Psoriasis and Psoriatic Arthritis Patients.

Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by periarticular bone loss and new bone formation. Current data regarding systemic bone loss and bone mineral density (BMD) in PsA are conflicting. The aim of this study was to evaluate bone microstructure and volumetric BMD (vBMD) in patients with PsA and psoriasis. We performed HR-pQCT scans at the ultradistal and periarticular radius in 50 PsA patients, 30 psoriasis patients, and 70 healthy, age- and sex-related controls assessing trabecular bone volume (BV/TV), trabecular number (Tb.N), inhomogeneity of the trabecular network, cortical thickness (Ct.Th), and cortical porosity (Ct.Po), as well as vBMD. Trabecular BMD (Tb.BMD, p = 0.021, 12.0%), BV/TV (p = 0.020, -11.9%), and Tb.N (p = 0.035, 7.1%) were significantly decreased at the ultradistal radius and the periarticular radius in PsA patients compared to controls. In contrast, bone architecture of the ultradistal radius and periarticular radius was similar in patients with psoriasis and healthy controls. Duration of skin disease was associated with low BV/TV and Tb.N in patients with PsA. These data suggest that trabecular BMD and bone microstructure are decreased in PsA patients. The observation that duration of skin disease determines bone loss in PsA supports the concept of subclinical musculoskeletal disease in psoriasis patients.

High incidence of disease recurrence after discontinuation of disease-modifying antirheumatic drug treatment in patients with psoriatic arthritis in remission.

OBJECTIVE: To investigate the possibility of drug-free remission in patients with psoriatic arthritis (PsA) in continuous remission. METHODS: Prospective observational study in disease-modifying antirheumatic drug (DMARD)-treated PsA patients in continuous disease remission (no musculoskeletal symptoms, no or minimal skin/nail disease) for at least 6 months. Demographic, disease-specific and ultrasound parameters were assessed at baseline. DMARDs (traditional or biologic) were discontinued at the initial visit, and patients were followed for a maximum of 6 months for recurrence of disease. RESULTS: 26 patients (methotrexate monotherapy: N=14; tumour necrosis factor inhibitors: N=12) with a mean age of 55.2 years, absence of musculoskeletal symptoms and minimal skin disease (mean Psoriasis Area Severity Index (PASI): 0.21) were enrolled. Incidence of recurrence of disease was high (N=20, 76.9%) and occurred rapidly (74.50±51.72 days) after treatment discontinuation. Male PsA patients were significantly more likely to lose remission. Long disease duration, more severe skin involvement and the presence of synovial hypertrophy by ultrasonographic examination at baseline decreased the likelihood for drug-free remission. Reinitiation of DMARDs promptly restored remission in all PsA patients with recurrence of disease. CONCLUSIONS: This study shows that the chance to reach drug-free remission in PsA patients is low. Discontinuation of DMARD therapy cannot be recommended in patients with PsA.

Inflammatory bone spur formation in psoriatic arthritis is different from bone spur formation in hand osteoarthritis.

OBJECTIVE: To investigate the different patterns of bone spur formation in psoriatic arthritis (PsA) and hand osteoarthritis (OA), using high-resolution peripheral quantitative computed tomography (QCT). METHODS: The study group comprised 70 subjects (25 patients with PsA, 25 patients with hand OA, and 20 healthy controls). The 2 patient groups were similar with regard to age and sex distribution and clinical involvement of the metacarpophalangeal (MCP) joints. All patients underwent high-resolution peripheral QCT scanning of the second, third, and fourth MCP joints of the dominantly affected hand. Demographic and disease-specific data were recorded, and the number, size, and distribution of bone spurs were assessed and compared between patients with PsA and patients with hand OA. RESULTS: The overall number and size of bone spurs were similar in patients with PsA and patients with hand OA. However, localization of lesions within individual joints was substantially different between patients with PsA and those with hand OA. In PsA, bone spurs dominated the radial sides of the joints (for the metacarpal head of the second joint, P < 0.001 versus hand OA; for the base of the second phalangeal joint, P < 0.001 versus hand OA), whereas the palmar and dorsal quadrants were the predilection sites in hand OA. Detailed anatomic analysis showed that bone spurs in the entheseal regions were prominent in patients with PsA but rare in patients with hand OA, and that bone spurs in patients with hand OA typically emerged at the cartilage-bone interphase and the joint margins. CONCLUSION: Our findings show that the overall number and size of bone spurs are similar in patients with PsA and patients with hand OA. Nonetheless, the anatomic sites of bone proliferation are different between these 2 groups of patients.

Differences in bone structure between rheumatoid arthritis and psoriatic arthritis patients relative to autoantibody positivity.

OBJECTIVE: To investigate whether trabecular and cortical bone structure differ between patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA). So far, no study has performed a detailed comparative analysis of bone structure in patients with RA and PsA. METHODS: 110 patients (60 RA, 50 PsA) received high-resolution peripheral quantitative CT of the distal radius. Demographic and disease-specific parameters including anti-rheumatic treatment, bone erosion status and previous fractures were recorded. RESULTS: RA and PsA patients were comparable in age, gender, body mass index, disease duration, disease activity, functional status, antirheumatic treatment and bone erosion status. No significant differences were found for volumetric bone mineral density (BMD), including total BMD (300±77 vs 316±62 mgHA/cm(3)), trabecular BMD (152±46 vs 165±40 mgHA/cm(3)) and cortical BMD (787±113 vs 818±76 mgHA/cm(3)) when comparing RA patients to PsA patients, respectively. However, in contrast to seronegative RA, seropositive RA showed significantly reduced trabecular BMD (p=0.007), bone volume per tissue volume (p=0.007) and trabecular number (p=0.044), as well as a strong trend towards higher trabecular inhomogeneity compared to PsA patients. In the regression analysis, higher age, female gender and presence of autoantibodies were independently associated with trabecular bone loss. CONCLUSIONS: Seropositive RA exhibits more profound changes in trabecular bone architecture than seronegative RA or PsA. The data support the concept that seropositive RA is a disease entity that is distinct from seronegative RA and PsA.

Bone anabolic changes progress in psoriatic arthritis patients despite treatment with methotrexate or tumour necrosis factor inhibitors.

OBJECTIVES: To investigate whether methotrexate or tumour necrosis factor inhibitors (TNFi) affect osteophyte formation in patients with psoriatic arthritis (PsA). METHODS: 41 patients with PsA were examined for the presence of osteophytes and erosions at the metacarpophalangeal joints by high-resolution micro-CT imaging. The size of each individual lesion was quantified at baseline and 1-year follow-up in PsA patients treated with TNFi (N=28) or methotrexate (N=13). Groups were comparable for age, sex, disease duration and activity and baseline burden of osteophytes. RESULTS: In total, 415 osteophytes (TNFi N=284, methotrexate N=131) were detected. Osteophyte size increased significantly from baseline to follow-up in the TNFi group (mean±SEM change +0.23±0.02 mm; p<0.0001) and the methotrexate group (+0.27±0.03 mm, p<0.0001). In both treatment groups, the majority of osteophytes showed progression (TNFi 54.3%, methotrexate 61.1%), whereas regression of lesions was rare (less than 10%). In contrast to osteophytes, clinical disease activity decreased in both groups of PsA patients and erosions showed an arrest of progression in both groups. CONCLUSIONS: Osteophytes progress in PsA patients treated with either methotrexate or TNFi. These data provide the first evidence that pathological bone formation in the appendicular skeleton of patients with PsA is not affected by current antirheumatic treatment strategies.

Association of brain functional magnetic resonance activity with response to tumor necrosis factor inhibition in rheumatoid arthritis.

OBJECTIVE: To test whether brain activity predicts the response to tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA). Since clinical and laboratory parameters have proven unsuccessful in predicting response, we followed a radically different concept, hypothesizing that response to TNFi depends on central nervous system activity rather than the clinical signs of disease. METHODS: Sequential testing by functional magnetic resonance imaging (MRI) of the brain, anatomic MRI of the hand, and clinical assessment of arthritis were carried out in 10 patients with active RA before and 3, 7, and 28 days after the start of TNFi treatment. RESULTS: Baseline demographic and disease-specific parameters were identical in TNFi responders and nonresponders. The mean ± SEM decrease in the Disease Activity Score in 28 joints after 28 days was -1.8 ± 0.3 in TNFi responders (n = 5) and -0.2 ± 0.1 in nonresponders (n = 5). Responders showed significantly higher baseline activation in thalamic, limbic, and associative areas of the brain than nonresponders. Moreover, brain activity decreased within 3 days after TNFi exposure in the responders, preceding clinical responses (day 7) and responses observed on the anatomic hand MRI (day 28). CONCLUSION: These data suggest that response to TNFi depends on brain activity in RA patients, reflecting the subjective perception of disease.

Repair of bone erosions in rheumatoid arthritis treated with tumour necrosis factor inhibitors is based on bone apposition at the base of the erosion.

OBJECTIVES: To investigate whether bone erosions in patients with rheumatoid arthritis (RA) show evidence of repair. METHODS: 127 erosions were identified in metacarpophalangeal joints 2-4 of the right hands of 30 RA patients treated with tumour necrosis factor inhibitors (TNFi) and 21 sex, age and disease activity-matched patients treated with methotrexate. All erosions were assessed for their exact maximal width and depth by high-resolution µCT imaging at baseline and after 1 year. RESULTS: All erosions detected at baseline could be visualised at follow-up after 1 year. At baseline, the mean width of bone erosions in the TNFi group was 2.0 mm; their mean depth was 2.3 mm, which was not significantly different from the methotrexate-treated group (width 2.4 mm; depth 2.4 mm). Mean depth of erosions significantly decreased after 1 year of treatment with TNFi (-0.1 mm; p=0.016), whereas their width remained unchanged. In contrast, mean depth and width of erosive lesions increased in the methotrexate-treated group. The reduction in the depth of lesions was confined to erosions showing evidence of sclerosis at the base of the lesion. Moreover, deeper lesions in the TNFi group were particularly prone to repair (-0.4 mm; p=0.02) compared with more shallow lesions. CONCLUSIONS: Bone erosions in RA patients treated with TNFi show evidence of limited repair in contrast to bone erosions in patients treated with methotrexate. Repair is associated with a decrease in the depth of lesions and sclerosis at the bases of the lesions. Repair thus emerges from the endosteal rather than periosteal bone compartment and probably involves the bone marrow.

A comparative study of periarticular bone lesions in rheumatoid arthritis and psoriatic arthritis.

BACKGROUND: Psoriatic arthritis (PsA) and rheumatoid arthritis (RA) are both destructive arthritides but may differ substantially in their periarticular bone changes. OBJECTIVES: To investigate the differences in the structural changes of periarticular bone in patients with PsA and RA by a high-resolution imaging technique designed to visualise the bone architecture. METHODS: 30 patients with PsA and 58 patients with RA received a µCT scan to compare structural bone changes in the metacarpophalangeal joints of the dominantly affected hand. Number, extent, form and distribution of bone erosions, osteophytes and cortical thinning were recorded. In addition, the size and depth of bone erosions and the size of osteophytes were determined. RESULTS: Patients with PsA and RA had the same number of bone erosions, but they were less severe and overall smaller in size and depth in PsA. Erosions in PsA were mostly Ω-shaped and tubule-shaped, whereas U-shaped lesions were most typical for RA. Erosions in PsA were more evenly distributed, lacking the strong preponderance for the radial sites found in RA. Osteophytes were increased in number, extent and size in PsA as compared with RA, often affecting the entire circumference of bone ('bony corona'). CONCLUSIONS: High-resolution µCT imaging shows profound differences in periarticular bone changes between PsA and RA. Smaller Ω-shaped and tubule-shaped bone erosions as well as large sometimes corona-shaped osteophytes are typical for PsA. These data suggest that mechanisms of bone repair may be more active in PsA than in RA.