The Indian Rheumatology Association

The Professional Organization of Rheumatologists and other Health Professionals in India

Clinical Science

Clinical Science
Compiled By

Dr Sanat Pathak
KEM Hospital Research Centre - Pune

Dr Debanjali
Kolkata

Dr Arvind Hegde
CMC, Vellore

Dr Sakir Ahmed
KIMS, Bhubhneshwar

 

Dr Nibha Jain
University Hospital - Leicester

Dr Dhaval
Medanta, Delhi

Dr Rutviz
SGPGI, Lucknow

Dr Suvrat Arya
Honorary fellow
The Royal Wolverhampton Trust NHS

Pediatric Rheumatology

A. October 2018 - January 2019

IgA vasculitis and vaccination risk

This study explored the potential relationship of IgA vasculitis developing after childhood vaccination. A cross over design compared the incidence of IgAV in the 3 month period immediately following vaccination to the 3 month period thereafter, stratified by season and infection. 167 children were enrolled the OR for IgAV occurring within the 3 month period was 1.6 (95% CI 0.8 – 3), which was not significant. Stratifications of IgAV risk as per month also did not reveal any significant associations, leading the authors to conclude that vaccination may not be a major etiological factor in childhood igAV. This study provides robust epidemiological data in studying the relationship between vaccination. This is especially relevant in areas where vaccination is culturally fought against and improves the case for universal vaccination.

Genetic insights in JIA

A comprehensive study on the genetic landscape in JIA was a felt need, and the authors studied polyarticular JIA in 2 independent cohorts. The GWAS identified 18 ‘hotspots’ of single nucleotide polymorphisms. On further functional analysis it was seen that the genes surrounding these hotspots were important for immunological processes and G protein coupled pathways. Novel variants in genes involved in histone modification and B cell DNAse were shown. This study explands the genetic variant repertoire of JIA and deepens understanding of genetic landscape of JIA. This is the first deep WGS to be done in JIA.

Long-term follow up of Canakinumab treatment in Systemic JIA

The authors published the results of the long term extensions of two phase 3 studies. 144 patients were analysed. 58% patients continued the drug for lack of efficacy. Those responding late were more likely to discontinue treatments. Nearly half achieved the JADAS low disease activity score at 2 years. 13 patients developed MAS. This study of the long term extension showed that response to canakinumab was sustained. A substantial number could reduce (22%) or stop (15%) steroids. Early response seems to predict long term outcome and thus can be a factor in deciding whether to continue the drug in these patients in the long term.

The Treat to Target strategy in JIA

Three treatment strategies ( sequential DMARD monotherapy, combination therapy with DMARD and combination with etanercept) were compared in 94% patients with JIA. At 2 years, a similar number of patients in all 3 groups had inactive disease (around70% each) and time to inactive disease was a median of 9 months. There was no difference in the time to flare (8 months) either. 40% could achieve drug free status. These data suggest that regardless of the initial choice of therapy, a treat to target approach works well in JIA too. The arms are reminiscent of the BEST trial in RA but interestingly the sequential monotherapy group seems to be as good as the others. Finally this paper suggests that T2T strategy is possible in JIA.

References

B. February - April 2019

Anakinra works like wonders for systemic JIA: results of a five year follow-up

The IL-1R antagonist helps achieve remission in around 33 days. And at one-year 3/4ths have inactive disease and 50% are off medication. By five years, 95% have inactive disease and 72% were in off-drug remission! The major advantage is the lack of steroid side-effects in growing children!

Ter Haar NM, van Dijkhuizen EHP, Swart JF, van Royen-Kerkhof A, El Idrissi A, Leek AP, de Jager W, de Groot MCH, Haitjema S, Holzinger D, Foell D, van Loosdregt J, Wulffraat NM, de Roock S, Vastert SJ, Treat-to-target using first-line recombinant interleukin-1 receptor antagonist monotherapy in new-onset systemic juvenile idiopathic arthritis: results from a five year follow-up study. Arthritis Rheumatol. 2019 Mar 8. doi: 10.1002/art.40865.

Addition of Cyclosporin help in Kawasaki disease refractory to only IVIg

175 patients deemed to be at risk for IVIg resistance were randomised to IVIg plus Cyclosporin or IVIg only. Incidence of coronary artery abnormalities was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0·46; 95% CI 0·25-0·86; p=0·010). No difference was found in the incidence of adverse events between the groups (9% vs 7%; p=0·78). Thus in patients with adverse prognostic factors, the addition of cyclosporin may be beneficial.

Hamada H, Suzuki H, Onouchi Y, Ebata R, Terai M, Fuse S, et al.; KAICA trial Investigators., Efficacy of primary treatment with immunoglobulin plus ciclosporin for prevention of coronary artery abnormalities in patients with Kawasaki disease predicted to be at increased risk of non-response to intravenous immunoglobulin (KAICA): a randomised controlled, open-label, blinded-endpoints, phase 3 trial. Lancet. 2019 Mar 16;393(10176):1128-1137.

Unmet needs and disparity in care of Juvenile arthritis across the world

In a global multi-centric study looking at the burden, characteristics and standards of care for juvenile idiopathic arthritis, patients with at least six months of follow-up were recruited. Each patient underwent retrospective and cross-sectional assessments, including measures of disease activity and damage and questionnaires on the wellbeing and quality of life of the children. The association between disease activity and damage and a country's gross domestic product (GDP) was explored.

9081 patients were enrolled at 130 centres in 49 countries, grouped into eight geographical areas. In south-east India, 1/3rd were systemic JIA and 1/3rd were enthesitis-related arthritis. While in Europe Oligoarticular comprised of more than 50% and in the US rheumatoid factor-negative polyarthritis was the most prevalent (31.5%).

Biological, disease-modifying antirheumatic drugs were prescribed more frequently in northern Europe and North America than in other geographical settings. Patients living in countries with lower GDP had higher disease activity and damage than those living in wealthier countries. Damage was associated with referral delay. There was greater disease burden in lower-resource settings.

Consolaro A, Giancane G, Alongi A, van Dijkhuizen EHP, Aggarwal A, Al-Mayouf SM,  et al. Paediatric Rheumatology International Trials Organisation. Phenotypic variability and disparities in treatment and outcomes of childhood arthritis throughout the world: an observational cohort study. Lancet Child Adolesc Health. 2019 Apr;3(4):255-263. doi: 10.1016/S2352-4642(19)30027-6.

S100 proteins in Polyarticular JIA on anti-TNF therapy

S100 A8/A9 and S100 A12 were evaluated in a prospective cohort of 137 Polyarticular JIA children(21) on anti-TNF therapy, for their ability to a) identify the maintenance of clinically inactive disease during therapy b) prediction of flare following withdrawal of therapy ( if patient has maintained clinically inactive disease for 6 months of anti-TNF therapy). Serum S100 levels were measured at baseline and at the time of anti‐TNF withdrawal. Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular‐course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare.

Hinze CH, Foell D, Johnson AL, Spalding SJ, Gottlieb BS, Morris PW, et al. Serum S100A8/A9 and S100A12 Levels in Children With Polyarticular Forms ofJuvenile Idiopathic Arthritis: Relationship to Maintenance of Clinically Inactive Disease During Anti-Tumor Necrosis Factor Therapy and Occurrence of Disease Flare After Discontinuation of Therapy. Arthritis Rheumatol. 2019 Mar;71(3):451-459.

Spondyloarthritis

A. October 2018 - January 2019

In the last quarter abundant data was reported from various cohorts in spondyloarthritis with major trials coming up.

Patients from ASAS and DESIRE cohort were studied for association between bone marrow oedema on MRI of the sacroiliac joints (MRI-SIJ) according to local readings in daily practice and the development of structural damage on radiographs of the SIJ (X-SIJ) in axial spondyloarthritis (axSpA). Baseline MRI and Xray along with follow-up Xray after a mean 4.6 years (ASAS) and 5.1 years (DESIR) was obtained. In multivariable analysis, baseline bone marrow oedema on MRI-SIJ was strongly associated with X-SIJ structural progression in both ASAS (odds ratio = 3.2 [95% CI: 1.3; 7.9]), and DESIR (odds ratio = 7.6 [95% CI: 4.3; 13.2]).1

An observational, cross-sectional and descriptive study of AS patients from the Spanish REGISPONSER database reported that in Caucasian AS patients, the presence of HLA-B27 was related to an earlier disease onset and higher family aggregation. Absence of HLA-B27 was related to a higher frequency of peripheral arthritis, dactylitis, and extra-articular manifestations. Being HLAB27 positive was not related to a higher burden of disease or anytime uveitis.2

Baseline data from the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis were explored. They observed smoking to be independently associated with an adverse disease profile in axial SpA, including worse fatigue, sleep, anxiety and depression, and higher odds of psoriasis. They also reported a paradoxical association between current smoking and reduced odds of uveitis.3

In a population based nationwide epidemiological study in Portugal’s mainland or Islands (Azores and Madeira), adults were screened in a three stage strategy (EpiReumaPt) which was found to be a good screening tool for SpA in general population without laboratory or imaging techniques.4

The SPondyloArthritis Caught Early cohort analysed gender specific approaches for diagnosing early axial SpA. While their data showed clear gender differences in early axSpA, they highlight that HLA-B27 and imaging are still key elements for diagnosis in both genders. the study did not suggest requirement of any separate diagnostic strategies for men and women.5

The SpondyloArthritis Caught Early (SPACE) cohort including patients with chronic back pain (393 patients) reported impaired spinal mobility in 66% patients compared to the general population. 6

Many papers on development of new scoring systems based on MRI or sonography were also reported.

Hip inflammation MRI scoring system (HIMRISS) uses bone marrow lesions (BML) and synovitis in SpA. Its reproducibility and reliability was studied by Yan Zheng et al who found it to be beneficial for early detection and fast quantification of inflammation.7

In the OMERACT MRI in Enthesitis Initiative study by Ashish J. Mathew et al Consensus definitions of key pathologies and three heel enthesitis multi-reader scoring exercises were done and Definitions for bone and soft tissue pathologies were agreed. They found the proposed definitions and heel enthesitis scoring system (HEMRIS) to be reliable among trained readers and promising for clinical trials.8

Javier E. Rosa et al studied the diagnostic value of color doppler ultrasound assessment of sacroiliac joints in patients with inflammatory low back pain. patients with IBP and suspected axial spondyloarthritis (SpA), but without a definitive diagnosis, were included with diagnosed cases controls. All patients underwent clinical evaluation, magnetic resonance imaging (MRI), and CDUS of sacroiliac joints (SIJ) within the same week. The sensitivity of CDUS for the diagnosis of axial SpA was 54% (95% CI 36.6–71.2%), specificity was 82% (95% CI 63.1–93.9%), PPV was 79% (95% CI 57.8–92.9%), and NPV was 59% (95% CI 42.1–74.4%).9 Hyoung Rae Kim et al in their study to investigate the relationship between low BMD in axSpA and new bone formation reported that low BMD and existing syndesmophytes at baseline were independently associated with the development of new syndesmophytes in young axSpA patients. 10

This quarter also observed follow-up data on use of biologics and radiographic progression.

The 4 year follow-up data of MEASURE 1 study was published showing the efficacy and radiological outcomes on Secukinumab. Of the 274 extension study participants who completed 240 week study Assessment of Spondyloarthritis International Society 20/40 (observed) were 79.7%/60.8% (150 mg), 71.0%/43.5% (75 mg) and 80.0%/76% (up-titrators; n = 25). Mean (S.D.) changes in mSASSS were 1.2 (3.91) (150 mg), 1.8 (4.32) (75 mg) and 1.6 (5.67) (up-titrators). No radiographic progression (mSASSS change from Baseline < 2) was observed in 79% of patients receiving either secukinumab dose. They also reported a consistent safety profile. 11

Patients with early axSpA who were treated with etanercept for up to 6 years in the ESTHER trial were studied for radiographic progression. They reported decelerated progression of structural damage in the SIJ on long‐term anti‐TNF therapy. Elevated CRP and presence of osteitis on MRI were independently associated with radiographic sacroiliitis progression.12

Another study although with much less sample size showed the opposite result.

Timothy J et al13 studied the temporal relationship between initiating biologic therapy and magnetic resonance imaging (MRI) scores of inflammation and structural damage in young (12-24 years) patients with spondyloarthritis. Patients treated with tumour necrosis factor inhibitor (TNFi) therapy with a minimum of one scan before and two after starting TNFi therapy (over ≥ 2 years) were included. Images of the sacroiliac joints were scored for inflammation and structural abnormalities (including erosions, fat metaplasia and fusion). Twenty‐nine patients aged 12‐23 years undergoing TNFi therapy were included. Inflammation scores were lower in patients on treatment (P=0.013), but there was no significant effect of time from TNFi initiation on inflammation (P=0.125). Conversely, there was no effect of treatment on fusion scores (P=0.285), but fusion scores increased with time from TNFi initiation (P=0.000). A similar pattern was observed for fat metaplasia. Thus according to this study although the inflammation was reduced there wasn’t a reduction in joint ankyloses.

Spinal radiographic progression in early axial Spondyloarthritis was reported from the DESIR cohort14. Two‐ and 5‐year mSASSS progression and development of new syndesmophytes (net change: number of patients with positive change minus number of patients with negative change divided by total number of patients) were assessed in subgroups defined at baseline according to the ASAS axSpA criteria and its arms, mNYC and the presence of syndesmophytes. They found that spinal radiographic progression, though limited in early axSpA, can be captured after 2 years. Inflammation and damage in the SIJ are associated with higher radiographic progression. The presence of baseline syndesmophytes strongly predicts the development of further structural damage already early in the disease. Freke Wink et al15 reported a 10 to 23% prevalence of hip involvement in AS patients which after 6 months of Anti TNF therapy showed improvement in tenderness and ultra-sonographic Doppler signals.

In a major study by Jordi Gratacós et al16 dose reduction was compared with standard dosing of TNF-inhibitors in axial spondyloarthritis. It was found that In patients in clinical remission for at least 6 months, dose reduction is non-inferior to full TNF inhibitor doses to maintain LDA after 1 year. Serious adverse events may be less frequent with reduced doses.

The GO-EASY17 study was analysed for the occurrence of acute anterior uveitis (AAU )in AS patients treated with Golimumab. They reported reduced occurrence and disease activity of AAU during treatment with GOL. A phase 3, randomised, double-blind, placebo-controlled superiority study of ixekizumab, (COAST-V)18 adult patients with inadequate response or intolerance to non-steroidal anti-inflammatory drugs, having an established diagnosis of radiographic axial spondyloarthritis, radiographic sacroiliitis centrally defined by modified New York criteria, and at least one spondyloarthritis feature according to the Assessment of SpondyloArthritis international Society (ASAS) criteria, were recruited from 84 sites. Ixekizumab was superior to placebo for improving radiographic axial spondyloarthritis signs and symptoms in patients not previously treated with bDMARDs In the randomized, double‐blind placebo‐controlled, Phase 3 trial of ixekizumab, adult patients with inadequate response/intolerance to 1 or 2 TNFi and an established diagnosis of axSpA were included. At 16 weeks they reported a rapid and significant improvement in the signs and symptoms of r‐axSpA versus placebo. However they also reported more frequent adverse event with Ixekizumab as compared to placebo.19 A randomised, placebo-controlled, phase 2 trial (TORTUGA) found Filgotinib to be efficacious and safe for the treatment of active AS.20

Two papers on quality of life were also reported. Yu Heng Kwan et al21 studies the quality of life domains in different SpA and found minimal differences between different subtypes.

Psychometric validation of the EuroQoL 5-dimension (EQ-5D) questionnaire in patients with spondyloarthritis was reported by Helen Hoi et al. EQ-5D scores achieved acceptable internal consistency and reliability. A ceiling effect was observed for all domains of the EQ-5D except for pain/discomfort. No floor effect was observed. Significant negative correlations were observed between ODI, HADS, BASFI, BASMI, BASDAI, and ASDAS-CRP and with EQ-5D. A higher disease activity was well-differentiated by EQ-5D, as with the disability and mental health scores.22

References

B. February - July 2019

Association between concomitant csDMARDs and clinical response to TNF inhibitors in overweight patients with axial spondyloarthritis.

The influence of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and body mass index (BMI) on circulating drug levels and clinical response to tumour necrosis factor inhibitor (TNFi) therapy in axial spondyloarthritis (axSpA) patients was studied in a prospective observational study during 1 year with 2 cohorts (Madrid and Amsterdam) including 180 axSpA patients treated with standard doses of infliximab or adalimumab. Patients were stratified by BMI, being 78 (43%) normal weight (18.5–24.9 kg/m2) and 102 (57%) overweight/obese (≥ 25.0 kg/m2). Seventy-nine patients (44%) received concomitant csDMARDs. The administration of concomitant csDMARDs (OR 3.82; 95% CI 1.06–13.84) and being normal weight (OR 18.38; 95% CI 2.24–150.63) were independently associated with serum TNFi drug persistence. Additionally, the use of concomitant csDMARDs contributed positively to achieve clinical response (OR 7.86; 95% CI 2.39–25.78) and remission (OR 4.84; 95% CI 1.09–21.36) in overweight/obese patients, but no association was found for normal-weight patients (OR 1.10; 0.33–3.58). Thus the use of concomitant csDMARDs with TNFi may increase the probability of achieving clinical response in overweight/obese axSpA patients.

Hernández-Breijo, B., Plasencia-Rodríguez, C., Navarro-Compán, V., Martínez-Feito, A., Jochems, A., Kneepkens, E. L., Balsa, A. (2019). Association between concomitant csDMARDs and clinical response to TNF inhibitors in overweight patients with axial spondyloarthritis. Arthritis Research & Therapy, 21(1), 66. https://doi.org/10.1186/s13075-019-1849-3

Patient Concerns and Perceptions Regarding Biologic Therapies in Ankylosing Spondylitis: Insights From a Large‐Scale Survey of Social Media Platforms.

Social media data was used to examine the knowledge, attitudes, and beliefs of AS patients regarding biologic therapies. Posts published on 601 social media sites between January 1, 2016, and April 26, 2017, were collected. In each post, both an AS keyword and a biologic were mentioned. To explore themes within the collection of posts in an unsupervised manner, a latent Dirichlet allocation topic model was fit to the data set. Each discovered topic was represented as a discrete distribution over the words in the collection, similar to a word cloud. The topics were manually reviewed to identify themes, which were confirmed using thematic data analysis. 27,416 social media posts were examined and 112 themes identified. The majority of themes (n = 67 [60%]) focused on discussions related to AS treatment. Other themes, including the psychological impact of AS, reporting of medical literature, and AS disease consequences, accounted for the remaining 40% (n = 45). In discussions regarding AS treatment, most topics involved biologics, and most subthemes involved side effects (e.g., fatigue, allergic reactions), biologic treatment attributes (e.g., dosing, frequency), and concerns about the use of biologics (e.g., increased cancer risk). Additional implicit patient needs (e.g., support) were identified using qualitative analyses. Social media revealed a dynamic range of themes governing AS patients' experience with and choice of biologic agents. The complexity of selecting biologics from among many such agents and navigating their risk/benefit profiles suggests the merit of creating online tools tailored to support patients' decision‐making concerning biologic therapies for AS.

Dzubur, E., Khalil, C., Almario, C. V., Noah, B., Minhas, D., Ishimori, M., Arnold, C., Park, Y. , Kay, J. , Weisman, M. H. and Spiegel, B. M. (2019), Patient Concerns and Perceptions Regarding Biologic Therapies in Ankylosing Spondylitis: Insights From a Large‐Scale Survey of Social Media Platforms. Arthritis Care Res, 71: 323-330. doi:10.1002/acr.23600

Assessment of the validity and reliability of the Jenkins Sleep Scale in ankylosing spondylitis

Jenkins Sleep Scale (JSS) Evaluation Questionnaire is a simple and easy to understand scale. Correlations with other functional parameters such as Multidimensional Assessment of Fatigue (MAF) scale, Ankylosing Spondylitis Quality of Life (ASQoL), Pittsburgh Sleep Quality Index (PSQI) were used to assess the convergent validity of JSS‐TR (Turkish version). Discriminant validity was also evaluated. Shapiro‐Wilk test was used as a test of normality. Sixty patients (24 female and 36 male) with mean age of 39.6 ± 10.8 years were recruited. The JSS‐TR took an average of 1.5 minutes (±30 seconds) to complete. JSS‐TR had the strongest correlation with PSQI scores (ρ = 0.75) and moderate‐strong correlations with MAF, ASQoL, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores. There was an insignificant correlation with non‐clinical parameters.

Duruoz, MT,  Ulutatar, F,  Ozturk, EC,  Unal‐Ulutatar, C,  Sanal Toprak, C,  Kayhan, O.  Assessment of the validity and reliability of the Jenkins Sleep Scale in ankylosing spondylitis. Int J Rheum Dis.  2019; 22: 275– 279. https://doi.org/10.1111/1756-185X.13447

Clinical and quality of life improvements with golimumab or infliximab in a real-life ankylosing spondylitis population: the QUO-VADIS study.

The QUO-VADIS was a prospective observational study evaluating the disease activity and health-related quality-of-life (HRQoL) in ankylosing spondylitis (AS) patients treated with golimumab (GLM) or infliximab (IFX, originator) during routine clinical care. The biologics-naïve AS patients were treated with GLM or IFX for 6 months. Disease activity (BASDAI, BASFI, ASAS, and ASDAS) and HRQoL improvement (≥5 points of SF-36 Physical Component Summary [PCS] score; PCS response) were measured. A Classification and Regression Trees (CART) analysis evaluated the association of baseline parameters with PCS response at 6 months.
963 patients (mean age 43 years, 61% male, 64% HLA-B27 positive) received ≥1 dose of medication (78% GLM; 22% IFX). The mean (SD) changes from baseline at month 6 of -2.7 (BASDAI) and -2.1 (BASFI) and 40% and 35% achievement of BASDAI50 and ASAS40 response, respectively, were observed. PCS response was achieved at month 6 in 52% of patients. Using CART analysis, baseline parameters (cut-off values) associated with HRQoL improvement were ASDAS (≥3.48), C-reactive protein (≥8.55 mg/L), age (≤35.5 years), and BASFI (≥1.15). This algorithm correctly identified 57.5% (sensitivity) of PCS responders (≥5 points) and 61.0% (specificity) of PCS non-responders (<5points) with ROC-AUC=0.61. Serious adverse events (AEs) occurred in 1.8% of patients with infections (7.7%) being the most common.

Van den Bosch F, Flipo RM, Braun J, Vastesaeger N, Kachroo S, Govoni M Clinical and quality of life improvements with golimumab or infliximab in a real-life ankylosing spondylitis population: the QUO-VADIS study. Clin Exp Rheumatol. 2019 Mar-Apr;37(2):199-207. Epub 2018 Jul 19.

Clinical and genetic characteristics of ankylosing spondylitis patients with peripheral arthritis at disease onset

The clinical and genetic characteristics associated with the presence of peripheral arthritis (PA) at disease onset in patients with ankylosing spondylitis (AS) was studied in456 Spanish AS patients, diagnosed according to the modified New York Criteria, with at least ten years of follow-up since initial disease onset were selected from the National Spondyloarthropathies Registry (REGISPONSER). 18.9% of AS patients initially presented PA. Clinical variables and 384 single nucleotide polymorphisms (SNPs) distributed in 190 genes were analysed.
AS patients with PA showed an earlier age of disease onset (p=0.021), longer disease duration (p=0.020) and longer duration of AS symptoms from onset (p=0.034) than AS patients without PA. We found significant associations with the presence of PA at disease onset in 14 SNPs located in 10 genes: HLA-DQB2 (rs2857210 and rs9276615), HLA-DOB (rs2857151, rs2621332 and rs1383261), JAK2 (rs7857730), IL-23R (rs11209008 and rs10489630), CYP1B1 (rs1056836), NELL1 (rs8176786), KL (rs564481), and MEFV (rs224204), IL-2RB (rs743777) and IL-1A (rs1800587).  Thus the subset of AS patients with PA at disease onset might have differentiation factors involved in disease pathogenesis.

Polo Y La Borda J1Szczypiorska M2Bartolomé N Clinical and genetic characteristics of ankylosing spondylitis patients with peripheral arthritis at disease onset.Clin Exp Rheumatol. 2019 Mar-Apr;37(2):215-221. Epub 2018 Sep 17.

Is it Useful to Repeat Magnetic Resonance Imaging of the Sacroiliac Joints After Three Months or One Year in the Diagnosis of Patients With Chronic Back Pain and Suspected Axial Spondyloarthritis?

The value of repeated magnetic resonance imaging (MRI) of the sacroiliac (SI) joints in diagnosing chronic back pain patients in whom axial spondyloarthritis (SpA) was suspected was studied.   Patients with chronic back pain (duration 3 months–2 years, age ≥16 years, age at onset <45 years) with ≥1 SpA feature who were included in the Spondyloarthritis Caught Early cohort underwent visits at baseline, at 3 months, and at 1 year. Visits included an evaluation of all SpA features and repeated MRI of SI joints. MRI‐detected axial SpA positivity (according to the definition from the Assessment of SpondyloArthritis international Society) was evaluated by 2 or 3 well‐trained readers who were blinded about clinical information. Of the 188 patients, 38.3% were male, the mean ± SD age was 31.0 ± 8.2 years, and the mean ± SD symptom duration was 13.2 ± 7.1 months. Thirty‐one patients (16.5%) had positive MRI findings in the SI joints at baseline. After three months and after one year, the MRI results had changed from positive to negative in 3 of 27 patients (11.1%) and 11 of 29 patients (37.9%), respectively, which was attributable in part to the initiation of anti-tumor necrosis factor therapy. Status changes from negative to positive were seen in 5 of 116 patients (4.3%) after three months and in 10 of 138 patients (7.2%) after one year. HLA–B27 positivity and male sex were independent determinants of the likelihood of a positive MRI scan at any time point (42% in HLA–B27+ men and 6% in HLA–B27− women). If the baseline results were negative, the likelihood of a positive scan at follow‐up was very low (≤7%). Thus conducting MRI scans after three months or after one year in patients with suspected early axial SpA is not diagnostically useful.

Bakker, P. A., Ramiro, S., Ez‐Zaitouni, Z. , Lunteren, M. , Berg, I. J., Landewé, R. , Ramonda, R. , Oosterhout, M. , Reijnierse, M. , Gaalen, F. A. and Heijde, D. (2019), Is it Useful to Repeat Magnetic Resonance Imaging of the Sacroiliac Joints After Three Months or One Year in the Diagnosis of Patients With Chronic Back Pain and Suspected Axial Spondyloarthritis?. Arthritis Rheumatol, 71: 382-391. doi:10.1002/art.40718

2018 APLAR axial spondyloarthritis treatment recommendations

Despite the availability of axial spondyloarthritis (SpA) recommendations proposed by various rheumatology societies, it was considered that a region‐specific guideline was of substantial added value to clinicians of the Asia‐Pacific region, given the wide variations in predisposition to infections and other patient factors, local practice patterns, and access to treatment across countries. Systematic reviews were undertaken of English‐language articles published between 2000 and 2016, identified from MEDLINE using PubMed, EMBASE, and Cochrane databases. The strength of available evidence was graded using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. Recommendations were developed through consensus using the Delphi technique. Fourteen axial SpA treatment recommendations were developed based on evidence summaries and consensus. The first 2 recommendations cover non‐pharmacological approaches to management. Recommendations 3 to 5 describe the following: the use of non‐steroidal anti‐inflammatory drugs as first‐line symptomatic treatment; the avoidance of long‐term corticosteroid use; and the utility of conventional synthetic disease‐modifying anti‐rheumatic drugs (csDMARDs) for peripheral or extra‐articular manifestations. Recommendation 6 refers to the indications of biological DMARDs (bDMARDs). Recommendation 7 deals specifically with screening for infections endemic to Asia, prior to use of bDMARDs. Recommendations 7 to 13 cover the role of bDMARDs in the treatment of active axial SpA and include related issues such as continuing therapy and use in special populations. Recommendation 14 deals with the utility of surgical intervention in axial SpA.

Tam, LS,  Wei, JC‐C,  Aggarwal, A, et al.  2018 APLAR axial spondyloarthritis treatment recommendations. Int J Rheum Dis.  2019; 22: 340– 356. https://doi.org/10.1111/1756-185X.13510

Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study

The infliximab biosimilar CT-P13 was approved for use in Crohn's disease after clinical comparison with originator infliximab in ankylosing spondylitis and rheumatoid arthritis;. This study investigated whether CT-P13 is non-inferior to infliximab in patients with Crohn's disease who were naive to biological therapy.

In this randomized, multicentre, double-blind, phase 3 non-inferiority study, patients with active Crohn's disease who had not responded to, or were intolerant to, non-biological treatments were enrolled. Patients were randomly assigned (1:1:1:1) to receive CT-P13 then CT-P13, CT-P13 then infliximab, infliximab then infliximab, or infliximab then CT-P13, with switching occurring at week 30. Patients received 5 mg/kg CT-P13 or infliximab at weeks 0, 2, 6, and then every eight weeks up to week 54. The primary endpoint was the proportion of patients with a decrease of 70 points or more in Crohn's Disease Activity Index (CDAI) from baseline to week 6. A non-inferiority margin of −20% was set (CT-P13 was non-inferior to infliximab if the lower limit of the two-sided 95% CI for the treatment difference was greater than −20). Between Aug 20, 2014, and Feb 15, 2017, 308 patients were assessed for eligibility, and 220 patients were enrolled: 111 were randomly assigned to initiate CT-P13 (56 to the CT-P13–CT-P13 group and 55 to the CT-P13–infliximab group) and 109 to initiate infliximab (54 to the infliximab–infliximab group and 55 to the infliximab–CT-P13 group). CDAI-70 response rates at week 6 were similar for CT-P13 (77 [69·4%, 95% CI 59·9 to 77·8] of 111) and infliximab (81 [74·3%, 95% CI 65·1 to 82·2] of 109; difference −4·9% [95% CI −16·9 to 7·3]), thereby establishing non-inferiority. Over the total study period, 147 (67%) patients experienced at least one treatment-emergent adverse event (36 [64%] in the CT-P13–CT-P13 group, 34 [62%] in the CT-P13–infliximab group, 37 [69%] in the infliximab–infliximab group, and 40 [73%] in the infliximab–CT-P13 group).

Prof Byong Duk Ye, MD ,Marina Pesegova, MD , Prof Olga Alexeeva, MD , Marina Osipenko, MD , Adi Lahat, MD , Andriy Dorofeyev, MD. Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study. The Lancet. March 28, 2019 DOI:https://doi.org/10.1016/S0140-6736(18)32196-2

Interleukin‐17A Inhibition Diminishes Inflammation and New Bone Formation in Experimental Spondyloarthritis.

The effect of tumor necrosis factor (TNF) and IL‐17A on osteogenesis was tested in an osteoblastic differentiation assay using SpA fibroblast‐like synoviocytes (FLS) differentiated with dexamethasone, β‐glycophosphatase, and ascorbic acid. IL‐17A blockade was performed in HLA–B27/human β2‐microglobulin (hβ2m)–transgenic rats, which served as a model for SpA in both prophylactic and therapeutic settings. Inflammation and new bone formation were evaluated by micro-computed tomography imaging, histologic analysis, and gene expression profiling. TNF and IL‐17A significantly increased in vitro osteoblastic differentiation. In vivo, prophylactic blockade of IL‐17A significantly delayed spondylitis and arthritis development and decreased arthritis severity. Anti–IL‐17A treatment was also associated with the prevention of bone loss and periosteal new bone formation. Therapeutic targeting of IL‐17A after the initial inflammatory insult also significantly reduced axial and peripheral joint inflammation. This treatment was again associated with a marked reduction in spinal and peripheral structural damage, including new bone formation. RNA sequencing of target tissue confirmed that IL‐17A is a key driver of the molecular signature of disease in this model and that therapeutic anti–IL‐17A treatment reversed the inflammatory signature and the selected gene expression related to bone damage. Both prophylactic and therapeutic inhibition of IL‐17A diminished inflammation and new bone formation in HLA‐B27/hβ2m–transgenic rats. Taken together with the ability of IL‐17A to promote osteoblastic differentiation of human SpA FLS, these data suggest a direct link between IL‐17A–driven inflammation and pathologic new bone formation in SpA.

Tok, M. N., Duivenvoorde, L. M., Kramer, I. , Ingold, P. , Pfister, S. , Roth, L. , Blijdorp, I. C., Sande, M. G., Taurog, J. D., Kolbinger, F. and Baeten, D. L. (2019), Interleukin‐17A Inhibition Diminishes Inflammation and New Bone Formation in Experimental Spondyloarthritis. Arthritis Rheumatol, 71: 612-625. doi:10.1002/art.40770

Effects of tapering tumor necrosis factor inhibitor on the achievement of inactive disease in patients with axial spondyloarthritis: a nationwide cohort study.

This study investigated the association between the extent of tapering tumor necrosis factor inhibitor (TNFi) and the likelihood of achieving inactive disease in patients with axial spondyloarthritis (axSpA). They analyzed 1575 1-year follow-up interval data of 776 axSpA patients treated with TNFi for more than 1 year in a nationwide observational cohort. At the baseline visit, 91.1% of the patients showed a high disease activity (ASDAS-CRP ≥ 2.1). A multivariable analysis showed that the likelihood of outcome achievement was comparable between the control and mild-tapering groups, but significantly decreased in the heavy-tapering group (vs. the control group, adjusted OR = 0.28, [95% CI, 0.08-0.94]). In contrast, the likelihood to achieve BASDAI50 response was not different among the groups. In the subgroup of patients who reached ASDAS-ID 1 year after TNFi treatment (n = 327), ASDAS-ID was observed in 66.1% of the subsequent intervals, and only the mild-tapering group showed a likelihood of target maintenance comparable with that of the control group (adjusted OR = 1.25 [0.41-3.80]). This likelihood decreased with an increase in ASDAS-CRP. So, mild tapering of TNFi has efficacy comparable with that of the standard-dose treatment for ASDAS-ID achievement in patients with axSpA.

Park JW, Kim H-A, Shin K, Park Y-B, Kim T-H, Song YW, et al. Effects of tapering tumor necrosis factor inhibitor on the achievement of inactive disease in patients with axial spondyloarthritis: a nationwide cohort study. Arthritis Research & Therapy [Internet]. 2019 Jul 4;21(1). Available from: http://dx.doi.org/10.1186/s13075-019-1943-6

Predictors of remission in patients with non-radiographic axial spondyloarthritis receiving open-label adalimumab in the ABILITY-3 study.

This analysis assessed baseline predictors of remission in patients with non-radiographic axial spondyloarthritis (nr-axSpA) who received open-label adalimumab therapy. ABILITY-3 enrolled 673 adult patients with nr-axSpA who had objective evidence of inflammation by MRI or elevated high-sensitivity C reactive protein at screening, active disease and an inadequate response to two or more non-steroidal anti-inflammatory drugs. Overall, 593 patients were included in the ASDAS ID and 596 in the ASAS PR analysis at week 12. Younger age (≤45 years), male sex, positive human leucocyte antigen (HLA)-B27 and higher Spondyloarthritis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score were consistent predictors of remission by both ASAS ID and ASDAS PR at week 12. Results were generally similar in the final visit analysis. Other variables did not consistently predict remission.

Sieper J, Landewé R, Magrey M, Anderson JK, Zhong S, Wang X, et al. Predictors of remission in patients with non-radiographic axial spondyloarthritis receiving open-label adalimumab in the ABILITY-3 study. RMD Open [Internet]. 2019 Jun;5(1):e000917. Available from: http://dx.doi.org/10.1136/rmdopen-2019-000917

Local sacroiliac injections in the treatment of spondyloarthritis. What is the evidence?

Local sacroiliac injections represent an available treatment option in spondyloarthritis (SpA). There is no synthetic data about efficacy of this procedure in SpA. Pubmed search retained 15 publications in spondyloarthritis, 12 with corticosteroids (total of 468 injections in 268 patients), including 2 small-sized controlled studies, and 3 with TNF blockers (24 patients in open studies). With steroids, the two controlled studies (with a total number of 30 patients only) demonstrated significant results over placebo. In open studies, good response was reported in more than 80% of the cases, with a mean duration of improvement over 8 months. Reduction of sacroiliac inflammation on MRI was also found in several studies after injection. There is no consensus about the technique of injection or the type of steroid injected. No particular safety concern was reported. Many limitations have to be considered in the interpretation of these results. So, this kind of procedure should be kept in the therapeutic armament in the current setting of costly targeted systemic treatments of spondyloarthritis. However, definition of a clear position in the treatment strategy needs further well-conducted studies.

Wendling D. Local sacroiliac injections in the treatment of spondyloarthritis. What is the evidence?. Joint Bone Spine. 2019.

Fatty corner lesions in T1-weighted magnetic resonance imaging as an alternative to sacroiliitis for diagnosis of axial spondyloarthritis.

A fatty corner lesion (FCL) is a well-demarcated fat infiltration in the corner of a vertebral body on T1 magnetic resonance imaging (MRI) sequence. It has been reported to be useful in the diagnosis of axial spondyloarthritis (axSpA). Two hundred and thirty eight axSpA patients and 62 non-axSpA patients with back pain were recruited from five rheumatology centres. Clinical, biochemical, and radiological parameters were collected and all patients underwent a MRI of the spine and sacroiliac (SI) joints. FCLs in vertebral bodies from C4 to L5 were scored. The number and location of FCLs were clustered together to determine an optimal combination for diagnosis. Results were compared with expert diagnosis as the "gold standard". FCLs of the anterior whole spine (AUC 0.62; p = 0.003) and anterior thoracic spine (AUC 0.64; p = 0.001) had diagnostic significance. Incorporating at least 5 whole spine FCLs into the imaging criteria of the Assessment of SpondyloArthritis international Society (ASAS) criteria for axSpA yielded a sensitivity of 91.6% and specificity of 91.9%. Similarly, applying at least 3 anterior thoracic FCLs to the imaging criteria of the ASAS axial SpA criteria yielded a sensitivity of 92.0% and specificity of 93.5%. To summarize, FCLs could be used to diagnose axial SpA. The presence of at least 3 anterior thoracic FCLs in T1-weighted MRI spine suggests a diagnosis of axial SpA without additional MRI of the SI joints.

Chung HY, Yiu RSW, Chan SCW, Lee KH, Lau CS. Fatty corner lesions in T1-weighted magnetic resonance imaging as an alternative to sacroiliitis for diagnosis of axial spondyloarthritis. BMC Rheumatology [Internet]. 2019 May 30;3(1). Available from: http://dx.doi.org/10.1186/s41927-019-0068-5

Performance of 18F-sodium fluoride positron emission tomography with computed tomography to assess inflammatory and structural sacroiliitis on magnetic resonance imaging and computed tomography, respectively, in axial spondyloarthritis.

To assess increased sacroiliac joint (SIJ) uptake on 18F-NaF PET/CT and to compare with MRI for inflammation and with CT scan for structural damages in a population of 23 patients with spondyloarthritis (SpA). Twenty-three patients with active SpA according to the Assessment of SpondyloArthritis international Society (ASAS) and/or modified NY criteria were included. All patients had a pelvic radiograph, MRI, and CT scan of the SIJ and 18F-NaF PET/CT examinations within a month, analyzed by three blinded readers. Structural sacroiliitis was observed on 7 radiographs and 10 CT scans; 10 MRIs showed inflammatory sacroiliitis, and 20 patients had a positive PET. The inter-reader reliability was good for the PET activity score and good to excellent for the SUVmax. A positive PET was not correlated with a positive MRI or with a structural sacroiliitis on CT scan. The PET-activity score and SUVmax were correlated with the SPARCC inflammation score but not with erosion or ankylosis scores on CT scan. The PET activity score and SUVmax had good correlations with inflammatory sacroiliitis but not with structural lesions on CT scan.

Raynal M, Bouderraoui F, Ouichka R, Melchior J, Morel O, Blum A, et al. Performance of 18F-sodium fluoride positron emission tomography with computed tomography to assess inflammatory and structural sacroiliitis on magnetic resonance imaging and computed tomography, respectively, in axial spondyloarthritis. Arthritis Research & Therapy [Internet]. 2019 May 14;21(1). Available from: http://dx.doi.org/10.1186/s13075-019-1903-1

Myositis

A. October 2018 - January 2019

In the last quarter studies on myositis mostly focused on the antibody profile and their clinical implications.

Young Kim Kyu et al1 described Anti‐TIF1γ antibody and the expression of TIF1γ in idiopathic inflammatory myopathies. They found TIF1α expression in the skin and TIF1γ in the muscle of DM was increased compared to controls. TIF1γ expression in the muscle of IIMs was related to anti‐TIF1γ antibody.

Progression-free survival (PFS) and overall survival rates were retrospectively evaluated in 32 consecutive patients with ARS-PM/DM-ILD by Hironao Hozumi et al2. The analysis demonstrated that first-line steroid + CNI therapy for patients with ARS-PM/DM-ILD significantly improved the PFS compared with steroid monotherapy, although there was no significant difference regarding longterm survival.

In the retrospective review of refractory Anti-HMGCR Immune mediated necrotizing myopathy by Océane Landon-Cardinal et al3, 3 out of 9 patients demonstrated stable or improved muscle strength ± decline in creatine kinase levels, or T2/short-tau inversion recovery hypersignal decrease on magnetic resonance imaging following RTX treatment.

M. Ogawa-Momohara et al4 reported the prognosis of dysphagia in DM patients. There was a significant negative correlation between cancer and dysphagia recovery (p=0.025). Other factors, such as age, sex, periods from onset to hospital visit or treatment, intravenous immunoglobulin (IVIG) or other immuno- suppressive therapy use did not significantly correlate with dysphagia recovery.

References

CD4+CXCR4+ T cell subset: a novel biomarker for idiopathic inflammatory myopathy-associated interstitial lung disease

The circulating CD4+CXCR4+ T cell subset was identified as a novel biomarker for idiopathic inflammatory myopathy-associated interstitial lung disease by K Wang et al. In their study,  peripheral percentage of CD4+CXCR4+ T cells was significantly associated with the severity of idiopathic inflammatory myopathy-associated interstitial lung disease and mortality.

Wang K, Zhao J, Chen Z, Li T, Tan X, Zheng Y, Gu L, Guo L, Sun F, Wang H, Li J, Wang X, Riemekasten G, Ye S. CD4+CXCR4+ T cells as a novel prognostic biomarker in patients with idiopathic inflammatory myopathy-associated interstitial lung disease. Rheumatology (Oxford). 2018 Dec 22.

B. February - July 2019

ACR/EULAR Classification criteria for IIM: Strengths and pitfalls

MJS Parker et al(19) explored the performance of the latest ACR EULAR IIM Classification criteria in an expert-defined ten year incident cohort at Salford Royal NHS Foundation Trust hospital. Among 1637 cases screened, 255 consensus expert opinion IIM cases were ultimately identified. On applying the EULAR/ACR classification criteria, the sensitivity to diagnose an IIM was 99.6% (95% CI 97.2, 100) and 80.9% (95% CI 76.0, 85.8) for the criteria cut-points of probable and definite diagnoses, respectively. There was a discrepancy in 94/255 cases, wherein IIM subtype differed between consensus expert opinion and classification criteria, in the group subtyped as PM by the EULAR/ACR criteria.

Parker MJS, Oldroyd A, Roberts ME, Lilleker JB, Betteridge ZE, McHugh NJ, et al. The performance of the European League Against Rheumatism/American College of Rheumatology idiopathic inflammatory myopathies classification criteria in an expert-defined 10-year incident cohort. Rheumatol Oxf Engl. 2018 Nov 28;

PET scan to differentiate between IBM and PM

Inclusion body myositis (IBM) is often a difficult diagnosis and to differentiate it from polymyositis (PM) may be truly challenging. Lilleker et al in this interesting paper came up with the suggestion of using PET scan for non-invasive differentiation of IBM from PM. Positron emission tomography can detect tissue deposits of amyloid and significantly increased intramuscular amyloid levels were found in IBM. In fact, amyloid levels generally correlated poorly with disease severity, muscle inflammation and fatty infiltration levels. Lillekar et al. conducted a clinical review, [18F]florbetapir positron emission tomography and MRI of skeletal musculature in 10 IBM and 6 PM patients. [18F]florbetapir standardised uptake value ratios were significantly higher in those with IBM compared with PM (total-[18F]florbetapir standardised uptake value ratio 1.45 vs 1.01, p=0.005). For total-[18F]florbetapir standardised uptake value ratios≥1.28, sensitivity, and specificity for IBM was 80% and 100%, respectively. So, they concluded that muscle amyloid imaging could differentiate between IBM and PM and could prove a useful future diagnostic modality. Immunosuppression does not modify disease progression in IBM, and hence, this non-invasive modality may help to avoid unnecessary exposure to potentially harmful treatments.

Lilleker JB, Hodgson R, Roberts M, et al[18F]Florbetapir positron emission tomography: identification of muscle amyloid in inclusion body myositis and differentiation from polymyositis Annals of the Rheumatic Diseases Published Online First: 13 February 2019. doi: 10.1136/annrheumdis-2018-214644

Long-term outcomes in Juvenile Myositis patients.

Juvenile idiopathic inflammatory myopathies (JIIM) are rare, chronic autoimmune muscle diseases of childhood, with the potential for significant morbidity. Data on long-term outcomes is limited. In this study, forty-nine adults with JIIM were assessed at two referral centers between 1994 and 2016. Features of active disease and damage at a cross-sectional assessment were obtained. Regression modeling was used to examine factors associated with long-term outcomes, defined by the presence of calcinosis or a higher adjusted Myositis Damage Index (MDI) score. At a median of 11.5 [IQR 4.5-18.9] years following diagnosis, median American College of Rheumatology (ACR) functional class was 2 [1.5-3.0], Health Assessment Questionnaire (HAQ) score was 0.4 out of 3.0 [0.0-1.0], and manual muscle testing (MMT) score was 229 out of 260 [212.6-256.8]. Median MDI score was 6.0 [3.5-8.9], with the most commonly damaged organ systems being cutaneous and musculoskeletal. Factors associated with an elevated MDI score were the presence of erythroderma and other cutaneous manifestations, disease duration, and ACR functional class. Calcinosis was present in 55% of patients. The strongest predictors of calcinosis were disease duration, periungual capillary changes, and younger age at diagnosis.

Tsaltskan V, Aldous A, Serafi S, Yakovleva A, Sami H, Mamyrova G, et al. Long-term outcomes in Juvenile Myositis patients. Seminars in Arthritis and Rheumatism [Internet]. 2019 Jun; Available from: http://dx.doi.org/10.1016/j.semarthrit.2019.06.014

The PRINTO evidence-based proposal for glucocorticoid tapering/discontinuation in new onset juvenile dermatomyositis patients.

Prednisone (PDN) in juvenile dermatomyositis (JDM), alone or in association with other immunosuppressive drugs, namely methotrexate (MTX) and cyclosporine (CSA), represents the first-line treatment option for new onset JDM patients. No clear evidence based guidelines are actually available to standardize the tapering and discontinuation of glucocorticoids (GC) in JDM. Aim of this study was to provide an evidence-based proposal for GC tapering/discontinuation in new onset juvenile dermatomyositis (JDM), and to identify predictors of clinical remission and GC discontinuation. New onset JDM children were randomized to receive either PDN alone or in combination with methotrexate (MTX) or cyclosporine (CSA). In order to derive steroid tapering indications, PRINTO/ACR/EULAR JDM core set measures (CSM) and their median absolute and relative percent changes over time were compared in 3 groups. Group 1 included those in clinical remission who discontinued PDN, with no major therapeutic changes (MTC) (reference group) and was compared with those who did not achieve clinical remission, without or with MTC (Group 2 and 3, respectively). A logistic regression model identified predictors of clinical remission with PDN discontinuation. Based on the median change in the CSM of 30/139 children in Group 1, after 3 pulses of methyl-prednisolone, GC could be tapered from 2 to 1 mg/kg/day in the first two months from onset if any of the CSM decreased by 50-94%, and from 1 to 0.2 mg/kg/day in the following 4 months if any CSM further decreased by 8-68%, followed by discontinuation in the ensuing 18 months. The achievement of PRINTO JDM 50-70-90 response after 2 months of treatment (ORs range 4.5-6.9), an age at onset > 9 years (OR 4.6) and the combination therapy PDN + MTX (OR 3.6) increase the probability of achieving clinical remission (p < 0.05).

Giancane G, Lavarello C, Pistorio A, Oliveira SK, Zulian F, et al. The PRINTO evidence-based proposal for glucocorticoids tapering/discontinuation in new onset juvenile dermatomyositis patients. Pediatric Rheumatology [Internet]. 2019 May 22;17(1). Available from: http://dx.doi.org/10.1186/s12969-019- 0326-5

Anti-Ro52 autoantibodies are associated with interstitial lung disease and more severe disease in patients with juvenile myositis.

Anti-Ro52 autoantibodies are associated with more severe interstitial lung disease (ILD) in adult myositis patients with anti-aminoacyl transfer (t)RNA synthetase autoantibodies. However, few studies have examined anti-Ro52 autoantibodies in juvenile myositis. The purpose of this study was to define the prevalence and clinical features associated with anti-Ro52 autoantibodies in a large cohort of patients with juvenile myositis. They screened sera from 302 patients with juvenile dermatomyositis (JDM), 25 patients with juvenile polymyositis (JPM) and 44 patients with juvenile connective tissue disease-myositis overlap (JCTM) for anti-Ro52 autoantibodies by ELISA. Disease course was more frequently chronic, remission was less common, and an increased number of medications was received in anti-Ro52 positive patients. Anti-Ro52 autoantibodies are present in 14% of patients with juvenile myositis and are strongly associated with anti-MDA5 and antiaminoacyl tRNA synthetase autoantibodies. In all patients with juvenile myositis, those with anti-Ro52 autoantibodies were more likely to have ILD. Furthermore, patients with anti-Ro52 autoantibodies have more severe disease and a poorer prognosis.

Sabbagh S, Pinal-Fernandez I, Kishi T, Targoff IN, Miller FW, Rider LG, et al. Anti-Ro52 autoantibodies are associated with interstitial lung disease and more severe disease in patients with juvenile myositis. Annals of the Rheumatic Diseases [Internet]. 2019 Apr 24;78(7):988–95. Available from: http://dx.doi.org/10.1136/annrheumdis-2018-215004

Nailfold capillary changes in adult new-onset dermatomyositis: a prospective cross-sectional study.

This study aimed at prospectively analysing nailfold capillaroscopy (NC) findings in new-onset dermatomyositis (DM) and to correlate NC findings with serum angiogenic cytokines and DM clinical and laboratory features. Twenty-three patients with DM who experienced < 12 months of symptoms were included in the study. To assess serum cytokine levels, 23 age-, sex-, and ethnicity-matched healthy volunteers were used. Significantly higher serum angiogenin (ANG) and vascular endothelial growth factor-1 (VEGF1) levels were observed in DM patients than in controls. Capillary density and avascular areas correlated positively and negatively, respectively, with serum levels of ANG. Moreover, the capillary density correlated inversely with the number of enlarged and giant capillaries and avascular areas. The number of enlarged capillaries correlated positively with patient and physician visual analogue scales (VAS), the presence of a facial rash, giant capillaries, and microhemorrhages. Giant capillaries had a positive correlation with physician and cutaneous VAS, enlarged capillaries, avascular areas, microhemorrhages and bushy capillaries, and a negative correlation with capillary density.

Microhemorrhages correlated positively with the "V-neck" sign and physician VAS. VEGF1 showed no relationship with the NC parameters with DM-related clinical and laboratory features. Additionally, 15 out of 23 patients were assessed prospectively after 3.21 years. All patients had a major clinical response with significant improvement in all NC parameters, except for enlarged and bushy capillaries.

Miossi R, de Souza FHC, Shinjo SK. Nailfold capillary changes in adult new-onset dermatomyositis: a prospective cross-sectional study. Clinical Rheumatology [Internet]. 2019 Apr 23; Available from: http://dx.doi.org/10.1007/s10067-019-04537-x

Comparison of the 2017 EULAR/ACR criteria with Bohan and Peter criteria for the classification of idiopathic inflammatory myopathies.

Bohan and Peter is the oldest criteria for the classification of idiopathic inflammatory myopathies (IIM). Recently, 2017 EULAR/ACR criteria were introduced which were validated against a control group. The objective of this study was to assess the performance of the 2017 EULAR/ACR criteria in retrospective cohort of adult and juvenile idiopathic inflammatory myopathies and compare with Bohan and Peter criteria. This was a retrospective study of patients clinically diagnosed to have IIM in a tertiary care center in the last 10 years. Hundred and eleven patients (87 females) were included in the study. Eleven patients had juvenile onset. Ninety-three patients (83.8%) were classified as probable/definite myositis using the Bohan and Peter criteria. Eighty-nine (80.2%) patients were classified as having probable/definite inflammatory myositis using the new criteria. Agreement between the two criteria was weak in our cohort (κ-0.331). Complete details of muscle biopsy were available in 52 patients. In this subgroup, 96% were classified by Bohan and Peter and 80.8% by EULAR/ACR criteria. Bohan and Peter classified 73% and EULAR/ACR 82% of patients when biopsy was excluded (n = 111). Both criteria classified over 90% of the patients with dermatomyositis. Forty-two patients were clinically diagnosed as polymyositis, of these 32 patients had myositis overlap syndrome. Bohan and Peter classified 66.7% and EULAR/ACR classified 64.3% in this subset. Bohan and Peter criteria had high sensitivity in the presence of muscle biopsy compared with EULAR/ACR. The performance of the EULAR/ACR criteria was similar to Bohan and Peter in the absence of muscle biopsy. Both criteria had poor sensitivity in polymyositis.

Pinto B, Janardana R, Nadig R, Mahadevan A, Bhatt AS, Raj JM, et al. Comparison of the 2017 EULAR/ACR criteria with Bohan and Peter criteria for the classification of idiopathic inflammatory myopathies. Clinical Rheumatology [Internet]. 2019 Mar 22;38(7):1931–4. Available from: http://dx.doi.org/10.1007/s10067-019-04512-6

Vasculitis

A. October 2018 - January 2019

Takayasu Arteritis:

Most of the clinical studies published in this last quarter focus on the clinical aspects of childhood onset TAK- describing the clinical, angiographic, treatment, activity, damage and overall prognosis of this disease.

Sezgin Sahin et al1 in their 15-year experience concluded that despite high usage rates of aggressive immunosuppressive therapy and biologic agents, almost half of the patients underwent interventional procedures. When medications failed, endovascular and surgical interventions were of great importance to avoid end‐organ ischemia. The performance of the new activity (DEI.Tak and ITAS2010) and damage indices (TADS) seems satisfactory.

Rajesh Vijayvergiya2described their experience from tertiary centre in north west India of 6 children with TA who were successfully managed with complex percutaneous interventions of the abdominal aorta and its major branches. Balloon dilatation and stent placement constitutes the mainstay of management of TA with stenosis of the large vessels.

Sergey Moiseev et al3 compared the childhood versus adult onset TAK and found that. Children had a lower female predominance, more frequent involvement of the aorta and renal arteries and arterial hypertension at presentation

Luyun Fan et al4 in their comprehensive analysis of 15 year data of 101 childhood TAK patients revealed an early 3% mortality at the first year and around 50% morbidity within 5 years after diagnosis. Hypertension, renal artery involvement, and revascularization based on anti-inflammation, antihypertension, and antiplatelet medications dominated c-TA with indications for optimistic prognosis. Patients with initial lower BMI level, a younger age at admission, stroke, and elevated CRP have a high risk of poor outcomes, requiring close c-TA monitoring and more aggressive management.

Value of contrast-enhanced ultrasonography of the carotid artery in 84 patients for evaluating disease activity in Takayasu arteritis by Ling-Ying Ma et al5 described Macaroni sign and entire artery involvement as characteristic findings of CEUS in TA. They concluded that the evaluation of vascular inflammation by CEUS is more sensitive than acute phase reactants. Neovascularization can still be observed in the vascular lesion sites of those who have reached clinical remission after treatment. Thus, CEUS can be used as an alternative method to assess disease activity for TA patients.

Giant cell arteritis and PMR

Lene Kristin et al6 have reported increased incidence of Giant cell arteritis in Urban areas.

Markus Aschwanden et al7 assessed the arterial wall morphology in Large vessel GCA by repeated US and concluded Regression of wall thickening within the LV is significantly less common than in the temporal artery and irrespective of clinical remission. Morphological regression does not seem to be a useful predictor for relapses.

In the same issue Pierluigi Macchioni et al8 evaluated the fluence of disease-related findings and treatment outcomes on survival in a population-based cohort of Northern Italian patients with GCA. They found that PMR at diagnosis and inflammation limited to the adventitia at Temporal artery biopsy appear to identify subsets of patients with more benign disease, while large vessel involvement at diagnosis is associated with reduced survival.

A case control study to determine the efficacy of methotrexate in management of GCA by Matthew JKoster et al9 showed the addition of MTX to GC decreased the rate of subsequent relapse by nearly 2-fold compared to patients taking GC alone. MTX may be considered as adjunct therapy in patients with GCA to decrease the risk of further relapse events.

In a retrospective review of 385 PMR patients by Alessandro Giollo et al10 showed the use of Amino bisphosphonates (N-BP) to be associated with the discontinuation of GC (adjusted HR 0.66, 95% CI 0.50–0.88), independent of age, initial GC dose, and osteoporosis.

Eun Seong Et al11 applied the 2012 EULAR/ACR criteria for PMR in Korean patients and found Eighty of 113 patients (81.6%) previously classified by Chuang and Hunder criteria or Healey criteria fulfilled 2012 EULAR/ACR criteria for PMR.

IgA Vasculitis

Cardiovascular, thromboembolic and renal outcomes in IgA vasculitis (Henoch-Schönlein purpura) is described by Alexander Tracy et al12 in a retrospective cohort of 2828 patients of adult onset IgAV and 10405 of childhood onset IgAV. Patients with IgAV are at increased risk of hypertension and chronic kidney disease (CKD) compared with individuals without IgAV; analysis restricted to adult-onset IgAV patients showed increased mortality. Appropriate surveillance and risk factor modification could improve long-term outcomes in these patients.

Pregnancy outcomes in women with a history of immunoglobulin A vasculitis by Johannes Nossent et al13 showed little impact of IgAv on fertility and flares during pregnancy.However, a history of IgAV associates with increased odds of spontaneous abortions, gestational hypertension and preterm delivery.

ANCA associated Vasculitis

The frequency of ANCA-associated vasculitis in a national database of hospitalized patients in China provided a spatial and ethnic clustering trend and an association between pollution and the frequency of AAV were observed14.

A systematic review of literature on successful treatment outcomes in pregnant patients with AAV by Pawan singh et al15 reported 137 pregnancies in 110 patients of AAV. They concluded that successful pregnancy can be achieved in such patients.

Andreas Kronbichler et al16 demonstrated Nasal carriage of Staphylococcus pseudintermedius in patients with granulomatosis with polyangiitis with unclear contribution to disease pathogenesis.

A randomized controlled study of efficacy and safety of Belimumbab and azathioprine for maintenance of remission in AAV by David Jayne et al17 did not reduce the risk of relapse with no new safety concerns.

Effect of disease activity at 3 and 6 months on long term outcomes in AAV by Seerapani et al18 suggests that disease status at three and six months may predict the risk of long‐term mortality and ESRF in AAV, and that these time points may be valid end‐points for induction trials in AAV. These results need to be validated in a larger dataset.

In a retrospective cohort study by Amy Kan et al19 a high incidence of arterial and venous thrombosis, particularly in the first year after diagnosis of AAV was reported.

Ruth J. Pepper et al20 published a prospective study of two groups of AAV where induction treatment consisted of two doses of rituximab with 3 months of cyclophosphamide and short course of steroids. They concluded early GC withdrawal to be effective for remission induction with reduced GC-related adverse events.

References

B. February - July 2019

Health related quality of life indices in GIACTA trial

Health related quality of life( HQRoL) indices  in 251 patients of Giant Cell Arteritis from the GIACTA trial ( toicilizumab in GCA trial) were recently reported by V Strand et al. Patients with GCA receiving tocilizumab 162mg s/c once a week along with 26 week prednisolone taper reported statistically significant and clinically meaningful improvement in SF-36 and FACIT-Fatigue scores compared with those receiving prednisone only in this trial and the improvements in the  same group led to recovery of HRQOL indices to levels  comparable to those of age and gender matched normative values at week 52 and exceeded normative values in five of eight domains(1).

Strand V, Dimonaco S, Tuckwell K, Klearman M, Collinson N, Stone JH.Health-related quality of life in patients with giant cell arteritis treated with tocilizumab in a phase 3 randomised controlled trial. Arthritis Res Ther. 2019 Feb 20;21(1):64. doi: 10.1186/s13075-019-1837-7.

Ciclosporin in Kawasaki disease at risk of IVIG resistance: KAICA trial

KAICA trial was a multi-centric randomised, open-label, blinded-endpoints trial in Japan on 175 Kawasaki disease patients. Patients at higher risk for intravenous immunoglobulin (IVIG) resistance were randomly assigned to IVIG plus ciclosporin (5 mg/kg per day for 5 days; study treatment) or IVIG. The primary outcome was the incidence of coronary artery abnormalities which was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0·46; 95% CI 0·25–0·86; p=0·010)(2).

Hamada H, Suzuki H, Onouchi Y, Ebata R, Terai M, Fuse S, et al. Efficacy of primary treatment with immunoglobulin plus ciclosporin for prevention of coronary artery abnormalities in patients with Kawasaki disease predicted to be at increased risk of non-response to intravenous immunoglobulin (KAICA): a randomised controlled, open-label, blinded-endpoints, phase 3 trial. Lancet Lond Engl. 2019 Mar 16;393(10176):1128–37.

The long awaited MYCYC trial results

In the MYCYC trial on 140 ANCA vasculitis patients, MMF displayed non-inferiority to cyclophosphamide for the primary endpoint of remission induction by 6 months ( 67% for MMF vs 61% for CYC). However, following remission, more relapses occurred in the MMF group (33%) compared with the cyclophosphamide group ( 19%).

Jones RB, Hiemstra TF, Ballarin J, Blockmans DE, Brogan P, Bruchfeld A, et al. Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomized, non-inferiority trial. Ann Rheum Dis. 2019 Mar;78(3):399–405.

RTX as induction and maintenance  agent in GPA: single centre prospective data from France

In a single centre study from France, wherein Rituximab was used in 114 GPA patients as both induction and maintenance agent and followed up for median period of 3.6 years, respective 2-year relapse-free survival and RTX retention rates were 85% and 78%. Serious infection and serious adverse event rates were 4.9 and 8.1 per 100 patient-years, respectively.

Puéchal X, Iudici M, Calich AL, Vivot A, Terrier B, Régent A, Cohen P, Jeunne CL, Mouthon L, Ravaud P, Guillevin L; French Vasculitis Study Group. Rituximab for induction and maintenance therapy of granulomatosis with polyangiitis: a single-centre cohort study on 114 patients. Rheumatology (Oxford). 2018 May 2.

Glucocorticoid receptor gene haplotypes and SNPs in AAV

AC Hessels et al investigated whether five potential functional haplotypes of the glucocorticoid receptor (GR) gene and a single-nucleotide polymorphism of 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) are associated with clinical outcome in ANCA-associated vasculitis. Haplotypes 1 and 4 of GR and a polymorphism of the HSD11B1 gene were associated with increased risk of 5 year mortality and risk of end-stage renal disease.

Hessels AC, Tuin J, Sanders JSF, Huitema MG, van Rossum EFC, Koper JW, van Beek AP, Stegeman CA, Rutgers A. Clinical outcome in antineutrophil cytoplasmic antibody-associated vasculitis and gene variants of 11β-hydroxysteroid dehydrogenase type 1 and the glucocorticoid receptor. Rheumatology (Oxford). 2018 Nov 14.

Need for higher titres of ANCA titres for the diagnosis of vasculitis

This study was performed to evaluate the clinical significance of ANCAs in the diagnosis of vasculitis. Bornstein et al. retrospectively studied the profile of 113 patients found to be positive for c-ANCA and anti-PR3 or p-ANCA and anti-MPO between 2007 and 2016 in a medical centre in Israel. Out of 113 patients, 60.1% of patients had no evidence of vasculitis. ELISA antibody titers were significantly higher among patients with vasculitis than those without. A significant proportion of patients with a positive C‐ANCA/PR3 or P‐ANCA/MPO do not have evidence of vasculitis, particularly those with low‐medium ELISA antibody titers. Using a higher threshold of ANCA titers may be required to improve specificity.

Bornstein G, Ben‐Zvi I, Furie N, Grossman C. Clinical significance of positive anti‐neutrophil cytoplasmic antibodies without evidence of anti‐neutrophil cytoplasmic antibodies‐associated vasculitis. Int J Rheum Dis. 2019;00:1–6. https://doi.org/10.1111/1756-185X.13483

Prognostic Factors in Anti-glomerular Basement Membrane Disease: A Multicenter Study from France

Authors report the overall and renal outcome in a French nationwide multicenter cohort of 119 patients with anti-glomerular basement membrane (anti-GBM) disease. Sixty-four patients (54%) had an exclusive renal involvement, 7 (6%) an isolated alveolar hemorrhage and 48 (40%) a combined renal and pulmonary involvement. Initial renal replacement therapy (RRT) was required in 78% of patients; 82% received plasmapheresis, 82% cyclophosphamide, and 9% rituximab. ANCA positive (28%) patients were older (70 vs. 47 years, p< 0.0001), less frequently smokers (26 vs. 54%, p = 0.03), and had less pulmonary involvement than ANCA- patients. The 5 years overall survival was 92%. Risk factors of death (n = 11, 9.2%) were age at onset [HR 4.10 per decade (1.89-8.88) p = 0.003], hypertension [HR 19.9 (2.52-157 0.2) p = 0.005], dyslipidemia [HR 11.1 (2.72-45) p = 0.0008], and need for mechanical ventilation [HR 5.20 (1.02-26.4) p = 0.047]. The use of plasmapheresis was associated with better survival [HR 0.29 (0.08- 0.98) p = 0.046]. At 3 months, 55 (46%) patients had end-stage renal disease (ESRD) vs. 37 (31%) ESRD- free and 27 (23%) unevaluable with follow-up < 3 months. ESRD patients were older, more frequently female and had a higher serum creatinine level at presentation than those without ESRD. ESRD-free survival was evaluated in patients alive without ESRD at 3 months (n = 37) using a landmark approach.

Marques C, Carvelli J, Biard L, Faguer S, Provôt F, Matignon M, et al. Prognostic Factors in Anti-glomerular Basement Membrane Disease: A Multicenter Study of 119 Patients. Frontiers in Immunology [Internet]. 2019 Jul 18;10. Available from: http://dx.doi.org/10.3389/fimmu.2019.01665

Imaging acquisition technique influences interpretation of PET vascular activity in large-vessel vasculitis.

Authors planned this study to determine the impact of imaging acquisition time on interpretation of disease activity on  18 F-fluorodeoxyglucose positron emission tomography (PET) in large-vessel vasculitis (LVV) and assess the relationship between clinical features and image acquisition time. Patients with giant cell arteritis (GCA) and Takayasu's arteritis (TAK) were recruited into a prospective, observational cohort. After a single injection of FDG, all patients underwent two sequential PET scans at one and two-hour time points. Images were interpreted for active vasculitis by subjective assessment, qualitative assessment, and semi-quantitative assessment. Agreement was assessed by percent agreement, Cohen's kappa, and McNemar's test. Multivariable logistic regression identified associations between PET activity and clinical variables.  79 patients (GCA  =  44, TAK  =  35) contributed 168 paired one and two-hour PET studies. A total of 94 out of 168 scans (56%) were interpreted as active at the one-hour time point, and 129 scans (77%) were interpreted as active at the two-hour time point (p < 0.01). Associations between clinical variables and PET activity categories (dual inactive, delayed active, dual active) were evaluated. Using multivariable nominal regression, clinically active disease was significantly more common in patients in the delayed active group (Odds Ratio 1.94, 95%CI 1.13-3.53; p  =  0.02) and the dual active group (Odds Ratio 1.71, 95%CI 1.06-2.93; p  =  0.04) compared to the dual inactive group. Imaging protocol significantly influences interpretation of PET activity in LVV. To conclude, a substantial proportion of patients with LVV have PET activity only detected by delayed imaging. These patients were significantly more likely to have concomitant clinically-determined active disease.

Quinn KA, Rosenblum JS, Rimland CA, Gribbons KB, Ahlman MA, Grayson PC. Imaging acquisition technique influences interpretation of positron emission tomography vascular activity in large-vessel vasculitis. Seminars in Arthritis and Rheumatism [Internet]. 2019 Jul; Available from: http://dx.doi.org/10.1016/j.semarthrit.2019.07.008

Antineutrophil cytoplasmic antibodies and their relationship with disease activity and presence of staphylococcal superantigens in nasal swabs in patients with GPA

Antineutrophil cytoplasmic antibodies (ANCAs) are considered a risk factor for granulomatosis with polyangiitis (GPA) exacerbation, especially when staphylococcal superantigens (SAgs) are present in nasal swabs. Their role in monitoring disease activity remains controversial. This study determined the relationship of ANCAs with disease activity and presence of SAgs in GPA patients. Among a total of 115 GPA patients hospitalized in the period 2009- 2016, we investigated the presence of SAgs and ANCA concentration. Blood samples and nasal swabs were taken at each visit (referred further to as episodes). Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). Authors analyzed 362 episodes. ANCAs were detected in 215 (59.4%), while SAgs were detected in 126 (34.8%) episodes. They found a significant correlation between the presence of ANCAs and disease activity (p = 0.0032), as well as between their level and GPA severity (r = 0.25363, p = 0.000001). They also determined that an ANCA values ≥ 138 Ru/ml were an indicator of active disease with high specificity and low sensitivity (84.4% and 37.3%, respectively). The relationship between ANCA presence and the presence of SAgs was not confirmed; however, when SAgs were analyzed based on the different types, ANCA levels were found to be significantly higher in the group with SAg type B (p = 0.031). There was no detectable evidence for the association between ANCA level and the presence of SAgs. Although monitoring ANCA levels as a marker of disease activity may be clinically relevant, GPA management cannot proceed on the basis of ANCA levels alone.

Fijolek J, Wiatr E, Petroniec V, Augustynowicz-Kopec E, Bednarek M, Gawryluk D, et al. Antineutrophil cytoplasmic antibodies and their relationship with disease activity and presence of staphylococcal superantigens in nasal swabs in patients having granulomatosis with polyangiitis: results of a study involving 115 patients from a single center. Clinical Rheumatology [Internet]. 2019 Jul 23; Available from: http://dx.doi.org/10.1007/s10067-019- 04693-0

Risk factors for cytomegalovirus infection in patients with antineutrophil cytoplasmic antibody-associated vasculitis.

Cytomegalovirus (CMV) infection under immunosuppression causes morbidity and mortality. This study aimed to elucidate risk factors for CMV infection in patients with antineutrophil cytoplasmic antibody- associated vasculitis (AAV). Patients with AAV who underwent remission induction treatment at Okayama University Hospital between 2006 and 2016 were retrospectively analyzed. The primary outcome was the development of CMV infection within 3 months. Of the 111 patients, 13 (11.7%) patients developed CMV infection. Patients with CMV infection were older (p = 0.030) and had a higher body mass index (p = 0.029) in comparison to those without CMV infection. A higher proportion had a severe form (p = 0.001) and granulomatosis with polyangiitis (GPA) (p = 0.001), as well as a higher Birmingham Vasculitis Activity Score (p = 0.018) and C-reactive protein (p = 0.018) levels at baseline. Using logistic regression analysis, severe form and GPA were independent risk factors (odds ratio [OR] = 9.68, 95% confidence interval [CI] = 1.92-60.23, and OR = 7.46, 95% CI = 1.46-47.60, respectively). In addition, patients with CMV infection were more likely than those without infection to be glucocorticoid- related diabetes mellitus (p = 0.025). This study highlights disease severity and subgroups of AAV as risk factors for CMV infection.

Morishita M, Sada K-E, Matsumoto Y, Hayashi K, Asano Y, Hiramatsu Asano S, et al. Risk factors for cytomegalovirus infection in patients with antineutrophil cytoplasmic antibody- associated vasculitis. Zaza G, editor. PLOS ONE [Internet]. 2019 Jul 10;14(7):e0218705. Available from: http://dx.doi.org/10.1371/journal.pone.0218705

2018 Update of the EULAR recommendations for the management of large vessel vasculitis.

Using EULAR standardised operating procedures for EULAR-endorsed recommendations, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 13 countries. This update has three overarching principles and 10 recommendations. Authors recommend that a suspected diagnosis of LVV should be confirmed by imaging or histology. High dose glucocorticoid therapy (40-60 mg/day prednisone-equivalent) should be initiated immediately for induction of remission in active giant cell arteritis (GCA) or Takayasu arteritis (TAK). They recommend adjunctive therapy in selected patients with GCA (refractory or relapsing disease, presence of an increased risk for glucocorticoid-related adverse events or complications) using tocilizumab. Methotrexate may be used as an alternative. Non-biological glucocorticoid-sparing agents should be given in combination with glucocorticoids in all patients with TAK and biological agents may be used in refractory or relapsing patients. They no longer recommend the routine use of antiplatelet or anticoagulant therapy for treatment of LVV unless it is indicated for other reasons.

Hellmich B, Agueda A, Monti S, Buttgereit F, de Boysson H, Brouwer E, et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Annals of the Rheumatic Diseases [Internet]. 2019 Jul 3;annrheumdis-2019-215672. Available from: http://dx.doi.org/10.1136/annrheumdis-2019-215672

Mycophenolate Mofetil Versus Cyclophosphamide for the Induction of Remission in Nonlife-Threatening Relapses of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Randomized, Controlled Trial.

Cyclophosphamide has been the mainstay of treatment of ANCA-associated vasculitis. However, cyclophosphamide has unfavorable side effects and alternatives are needed. Evidence suggests that mycophenolate mofetil can induce sustained remission in nonlife-threatening disease. Authors conducted a multicenter randomized, controlled trial. Participants with a first or second relapse of ANCA- associated vasculitis were randomized to induction treatment with cyclophosphamide or mycophenolate mofetil both in combination with glucocorticoids. Maintenance therapy consisted of azathioprine in both arms. Primary outcome was remission at 6 months, and secondary outcomes included disease-free survival at 2 and 4 years. Eighty-four participants were enrolled, of whom 41 received mycophenolate mofetil and 43 received cyclophosphamide. Eighty-nine percent of participants were proteinase 3-ANCA positive. At 6 months, 27 (66%) mycophenolate mofetil-treated participants versus 35 (81%) cyclophosphamide-treated participants were in remission (P=0.11). Disease-free survival rates at 2 and 4 years were 61% and 39% for cyclophosphamide, respectively, and 43% and 32% for mycophenolate mofetil, respectively (at 4 years, log rank test, P=0.17). Mycophenolate mofetil might be an alternative to cyclophosphamide for the treatment of selected patients with nonlife-threatening relapses.

Tuin J, Stassen PM, Bogdan DI, Broekroelofs J, van Paassen P, Cohen Tervaert JW, et al. Mycophenolate Mofetil Versus Cyclophosphamide for the Induction of Remission in Nonlife-Threatening Relapses of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis. Clinical Journal of the American Society of Nephrology [Internet]. 2019 Jun 28;14(7):1021–8. Available from: http://dx.doi.org/10.2215/CJN.11801018

Comparative study of infliximab versus adalimumab in refractory uveitis due to Behçet's disease

Authors conducted an open-label multicenter study of IFX or ADA-treated patients with BD-uveitis refractory to conventional non-biologic treatment. IFX or ADA were chosen as first biologic treatment based on physician and patient agreement. Dosing schedule was: IFX: 3-5 mg/kg i.v. at 0, 2 and 6 weeks and every 4-8 weeks thereafter, and ADA: 40 mg/s.c./every other week without loading dose. 177 patients (316 affected eyes) were included. IFX was used in 103 and ADA in 74 cases. After one year of therapy, an improvement in all ocular parameters in both groups was observed. However, ADA therapy yielded better outcome in some parameters that in some cases yielded statistically significant differences: anterior chamber inflammation (78.18% in IFX-treated vs 92.31%in ADA-treated; p=0.06), vitritis (78.95% vs 93.33%; p=0.04), retinal vasculitis (97% vs 95%; p=0.28), macular thickness (264.89±59.74 vs 250.62±36.85; p=0.15), best-corrected visual acuity (0.67±0.34 vs 0.81±0.26; p=0.001), and drug retention (84.95% vs 95.24%; p=0.042). Although IFX and ADA yields efficacy refractory BD uveitis, ADA appears to be associated with better outcome than IFX after one-year follow-up.

Atienza-Mateo B, Martín-Varillas JL, Calvo-Río V, Demetrio-Pablo R, Beltrán E, Sánchez- Bursón J, et al. Comparative study of infliximab versus adalimumab in refractory uveitis due to Behçet’s disease, National multicenter study of 177 cases. Arthritis & Rheumatology [Internet]. 2019 Jun 25; Available from: http://dx.doi.org/10.1002/art.41026

Rheumatoid arthritis

A. October 2018 - January 2019

Disease activity measurement:

Tender joint count and swollen joint counts were calculated and compared to synovitis on ultrasound, disease activity parameters and patient reported outcomes. While swollen joint count predicted higher disease activity, only tender joints predicted lower levels of inflammation by US. TJC only correlated with patient related outcomes. Thus the TJC may be providing misleading information about inflammatory activity, and it’s inclusion in many disease activity compound scores needs to be carefully considered.

Hand osteoarthritis and disease activity:

Inflammation in joints is purported to be one of the risk factors for osteoarthritis. Patients with RA, with or without Distal interphalangeal joint OA were examined for risk factors. Age, female sex and BMI predicted the development of DIP OA but ACPA or RF positivity did not. On follow up for median of 4.5 years, there was no relevant effect size of rheumatoid disease activity associated with OA progression. The role of inflammation is therefore still unclear.

Chronic opioid use in Rheumatoid arthritis:

A prevalence and predictors study of trends of opioid use in 33000 patients with RA (over 13 years; 2002- 2015) showed alarming increase in opioid use; from 7.4% patients to 16.9%. Predictably, pain VAS and damage predicted the use of opioids. Interestingly, Asian race predicted less opioid use, possibly reflecting cultural beliefs about addictive drugs.

Venous thromboembolism in patients on Tofacitinib:

It is believed that JAK inhibition is associated with increased risk of clotting. In 34000 patients of RA, crude incidence rate of developing VTE was 1.1 in those who had received tofacitinib versus 0.9 in those who did not. While they had a numerically higher rate, it did not achieve statistical significance. Finally, the incidence rates are small (overall < 1%).

References

B. February - April 2019

Machine learning used to score disease activity in RA using ultrasound

OMERACT-EULAR Synovitis Scoring (OESS) system was used to design a neural network (machine learning) to score images across all four of the OESS systems Doppler US scores (0-3). Information was obtained from 1342 Doppler US images and the performance of the neural network was tested on 176 new images.

The neural network achieved an average per class accuracy of 75.0% and a quadratically weighted kappa score of 0.84 as compared to an expert rheumatologist sonographer.

Andersen JKH, Pedersen JS, Laursen MS, Holtz K, Grauslund J, Savarimuthu TR, Just SA. Neural networks for automatic scoring of arthritis disease activity on ultrasound images. RMD Open. 2019 Mar 30;5(1):e000891. doi: 10.1136/rmdopen-2018-000891. eCollection 2019.

OMERACT update: Long-term outcomes in RA

The OMERACT group for RA Longterm Observational Studies Special Interest Group have proposed that long term outcomes need to be different from short term ones. A systematic review and qualitative research were carried out. The final domains identified were pain, physical functioning, participation (i.e., work, social), long-term symptoms, fertility/family planning, emotional well-being, coping, financial status, and adverse events including death.

Lopez-Olivo MA, Negrón JB, Zogala RJ, Carmona L, Criner K, Goel N, Gonzalez-Lopez L, Ingegnoli F, Leong A, March L, Shea B, Strand V, Tugwell P, Westrich-Robertson T, Zamora NV, Christensen R, Suarez-Almazor ME. Core Outcome Sets Specifically for Longterm Observational Studies: OMERACT Special Interest Group Update in Rheumatoid Arthritis J Rheumatol. 2019 Mar 1.

Abatacept in the peri-operative period in RA patients undergoing hip or knee arthroplasty

In a study of 1780 RA patients receiving IV abatacept, stopping abatacept therapy < 4 weeks or > 4 weeks prior to hip or knee arthroplasty , showed no significant increase in post-operative infection. No significant differences were seen in the rates of 1-year prosthetic joint infection or 30-day readmission between patients who received abatacept <4 weeks or >4 weeks before surgery. However, the use of steroids within three months before surgery predisposed these patients to an increased risk of infection.

George MD, Baker JF, Winthrop K, Alemao E, Chen L, Connolly S, et al. Timing of Abatacept Before Elective Arthroplasty and Risk of Postoperative Outcomes. Arthritis Care Res. 2019 Feb 11;

RA and assisted reproductive techniques

In a Danish study on the impact of RA on the outcome of assisted reproductive techniques was investigated. The study cohort comprised of all women with an embryo transfer during 1994 through 2017, including 1149 embryo transfers in women with rheumatoid arthritis, and 198 941 embryo transfers in women without rheumatoid arthritis. The adjusted OR (aOR) for a live birth per embryo transfer in women with rheumatoid arthritis, relative to women without rheumatoid arthritis, was 0.78 (95% CI 0.65 to 0.92).

Nørgård BM, Larsen MD, Friedman S, Knudsen T, Fedder J. Decreased chance of a live-born child in women with rheumatoid arthritis after assisted reproduction treatment: a nationwide cohort study. Ann Rheum Dis. 2019 Mar;78(3):328–34.

RCT on primary prevention of CVD risk factors in RA

A distinctive trial was published recently which aimed to study the impact of primary prevention for atherosclerosis in RA patients.It was an open-label, randomised controlled trial, wherein  320 patients with RA aged <70 years without prior CVD or diabetes mellitus were randomised 1:1 to either a treat-to-target approach or usual care of traditional CVD risk factors. The primary outcome studied was a change in carotid intima-media thickness (cIMT) over five years. The mean cIMT progression was significantly reduced in the treat-to-target group compared with usual care and cardiovascular events occurred in significantly lesser patients in the treat-to-target group vs in those receiving usual care  (1.3% vs 4.7%).

Burggraaf B, van Breukelen-van der Stoep DF, de Vries MA, Klop B, Liem AH, van de Geijn G-JM, et al. Effect of a treat-to-target intervention of cardiovascular risk factors on subclinical and clinical atherosclerosis in rheumatoid arthritis: a randomised clinical trial. Ann Rheum Dis. 2019 Mar;78(3):335–41.

Biologicals in older RA patients: efficacy and safety

In a systematic review and meta-analysis of 24 studies ( RCT and observational studies of minimum six months duration) representing 63,705 RA patients receiving biologicals, showed worse efficacy outcomes in older patients. The pooled OR of infection and ADRs with anti-TNF agents in older compared to young RA patients was OR 1.59 (95% CI: 1.45–1.76) and 1.40 (95% CI: 1.23–1.61) respectively.

Dalal DS, Duran J, Brar T, Alqadi R, Halladay C, Lakhani A, et al. Efficacy and safety of biological agents in the older rheumatoid arthritis patients compared to Young: A systematic review and meta-analysis. Seminar Arthritis Rheum. 2019;48(5):799–807.

Mortality in Early RA patients…same as the general population

Poppelaars et al. compared the mortality in the COBRA-trial up to 2017 to a reference sample of the general population in the Netherlands. The duration of follow-up was a mean of 23 years. A total of 44 patients (28%; SMR 0.80) died in the COBRA trial, and 55 patients (36%) died in the general population. Five factors were significantly associated with increased mortality hazard: damage progression at 28 weeks; high Health Assessment Questionnaire (HAQ) score, absence of HLA-DR 2 or 3, and disease duration from the start of complaints. This prospective trial cohort study of early RA is one of the first to show similar mortality compared with the general population after 23 years of follow-up.

Poppelaars PB, van Tuyl LHD, Boers M Normal mortality of the COBRA early rheumatoid arthritis trial cohort after 23 years of follow-up. Annals of the Rheumatic Diseases Published Online First: 26 February 2019. doi: 10.1136/annrheumdis-2018-214618

Risk of Coronary events increased both in RA patients and their siblings.

Westerlind et al. identified a cohort of patients with new-onset RA 1996–2016, age- and sex-matched (5:1) general population comparator subjects, full siblings of RA and comparator subjects, and documented the incident acute coronary events (ACE) in them. A total of 8,109 patients with incident RA and 11,562 full siblings of them were collected. Compared with the general population, the HR of ACS in RA was 1.46 and 1.22 among their siblings. The increased risks seemed confined to seropositive RA and no significant risk increase was observed among siblings of patients with seronegative RA. So, it can be suggested that siblings of patients with RA are at increased risk of ACS, suggesting shared susceptibility between RA and ACS.

Westerlind H, Holmqvist M, Ljung L, et al Siblings of patients with rheumatoid arthritis are at increased risk of acute coronary syndrome Annals of the Rheumatic Diseases Published Online First: 20 February 2019. doi: 10.1136/annrheumdis-2018-214828

Subclinical Myocardial inflammation in RA

Amigues et al. studied prevalence and correlates of subclinical myocardial inflammation in patients with rheumatoid arthritis. One hundred and nineteen RA patients without known cardiovascular diseases underwent cardiac 18‐fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET‐CT). Visually assessed FDG uptake was observed in 39% of the 119 RA patients, and 18% had abnormal quantitatively assessed myocardial FDG uptake (i.e., mean of the mean standardized uptake value (SUV) ≥3.10 units. The SUVmean was significantly higher in patients with a CDAI score of ≥10 (moderate‐to‐high disease activity) as compared with those with lower CDAI scores. A subset of eight RA patients who had to escalate their disease‐modifying antirheumatic drug (DMARD) therapy. underwent a second FDG PET‐CT scan after 6 months. The myocardial SUV was found to decrease in these patients, paralleling the decrease in CDAI. So, this group concluded that subclinical myocardial inflammation is frequent in patients with RA, is associated with RA disease activity, and may decrease with RA therapy.

Amigues I,Aylin Tugcu A, Russo C et al Myocardial Inflammation measured Using 18‐Fluorodeoxyglucose Positron Emission Tomography With Computed TomographyIs Associated With Disease Activity in Rheumatoid Arthritis. Arthritis and Rheumatology https://doi.org/10.1002/art.40771

Fatigue in RA- The RAFT theory

Hewlett et al. randomized 333 RA patients with fatigue severity>6/10 into two arms- RAFT (Reducing Arthritis Fatigue: clinical Teams using CB approaches) arm and control arm. In the RAFT arm, patients were offered seven sessions of cognitive behavioural therapies, by pairs of trained rheumatology occupational therapists/nurses. At 26 weeks, the adjusted difference between arms for fatigue impact change (Bristol RA Fatigue Effect Numerical Rating Scale, BRAF-NRS Effect −0.59, 95% CI –1.11 to -0.06) favoured RAFT. So, multiple RA fatigue impacts can be improved for 2 years by rheumatology teams delivering a group programme using cognitive behavioural approaches.

Hewlett S, Almeida C, Ambler N, et al Reducing arthritis fatigue impact: two-year randomised controlled trial of cognitive behavioural approaches by rheumatology teams (RAFT)Annals of the Rheumatic Diseases Published Online First: 06 February 2019. doi: 10.1136/annrheumdis-2018-214469

Association of anti-CCP antibodies with reduced bone density- data from the BARFOT cohort

Ingiäld Hafström et al. endeavored to study the role of anti-CCP in both bone loss and pain in rheumatoid arthritis. Baseline data from the BARFOT (Better Anti-Rheumatic PharmacOTherapy) cohort, which consists of patients with RA with a disease duration of 1 year or less, were analysed. Of the 657 patients, 58% were anti-CCP positive, 37% had osteopenia in the lumbar spine, 29% had osteopenia in the hip and 61%  had unacceptable pain at diagnosis Patients positive for anti-CCP had significantly more frequently osteopenia in the femoral neck and Ward's triangle compared with anti-CCP-negative patients. Anti-CCP was not associated with unacceptable pain. These data show that in patients with early RA, anti-CCP positivity was independently associated with osteopenia in the femoral neck and/or Ward, but not in the lumbar spine. 

Ingiäld Hafström, Sofia Ajeganova, Kristina Forslind and Björn Svensson. Anti-citrullinated protein antibodies are associated with osteopenia but not with pain at diagnosis of rheumatoid arthritis: data from the BARFOT cohort.Arthritis Research & Therapy201921:45 https://doi.org/10.1186/s13075-019-1833-y

Prophylactic effect of sulfasalazine against Pneumocystis pneumonia in patients with rheumatoid arthritis

Nunokawa et al. conducted this nested case-control study to evaluate the prophylactic effect of sulfasalazine against Pneumocystis jirovecii pneumonia (PJP) among rheumatoid arthritis (RA) patients. Data were extracted from a nationwide Japanese multicenter RA database from 18,668 participants between 2005 to 2014. Sixty cases of PJP, 356 unmatched controls, and 337 matched controls were selected. None of the cases received sulfasalazine before PJP onset. Comparison of the cases with both matched and unmatched controls revealed that sulfasalazine use carried a decreased risk of PJP. In an analysis of the cases and unmatched controls who did not receive sulfasalazine, an increased risk of PJP was associated with lung disease and the use of glucocorticoid, methotrexate, and tumor necrosis factor inhibitors. The authors thus concluded that the use of Sulfasalazine has a protective role against PJP in RA patients.

Takahiro Nunokawa, Naoto Yokogawa, Kota Shimada, Prophylactic effect of sulfasalazine against Pneumocystis pneumonia in patients with rheumatoid arthritis: A nested case-control study, Seminars in Arthritis and Rheumatism, Volume 48, Issue 4, 2019, Pages 573-578, https://doi.org/10.1016/j.semarthrit.2018.05.013

Anti-nuclear antibody development is associated with poor treatment response to bDMARDs in patients with rheumatoid arthritis

It has been well known that TNF-α inhibitor (TNFi) treatment for patients with rheumatoid arthritis (RA) is associated with anti-nuclear antibody (ANA) development. But whether this ANA development is associated with poor treatment outcome in RA patients was still an unproven fact. Ishikawa et al 7 recruited Japanese RA patients treated with (n = 657) or without (n = 211) bDMARDs as a first line bDMARD were enrolled from a single center cohort. ANA development (≥2 times baseline levels) at 3 months and at 6–12 months after bDMARDs initiation was significantly associated with insufficient response at 3–12 months (odds ratio (OR)=3.51, p = 0.020) and at 12–24 months (OR = 3.16, p = 0.038), respectively. The use of Infliximab and other TNFi were associated with ANA development, whereas non-TNFi were not. So, the authors concluded that ANA development could be a marker of poor treatment response in RA patients undergoing bDMARDs treatment. 

Yuki Ishikawa, Motomu Hashimoto, Hiromu Ito et al. Anti-nuclear antibody development is associated with poor treatment response to biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis,Seminars in Arthritis and Rheumatism, 2019, https://doi.org/10.1016/j.semarthrit.2019.02.003

Serum sclerostin levels do not correlate with disease activity and BMD in RA

This study aimed to assess serum sclerostin in rheumatoid arthritis (RA) and its correlation with disease activity and bone mineral density (BMD). RA patients (>18 years) fulfilling the ACR/EULAR (2010) criteria for RA were included in this study by Dhakad et al. Serum sclerostin was significantly higher in patients compared to controls, but it did not correlate with ESR, CDAI, and BMD at the lumbar spine, femur neck, and wrist. Serum sclerostin levels were elevated in RA patients but did not correlate with disease activity and BMD.

Urmila Dhakad, Rasmi Ranjan Sahoo, Akhil Pawan Goel et al. Serum sclerostin levels in rheumatoid arthritis and correlation with disease activity and bone mineral density. DOI: 10.4103/injr.injr_113_18

Systemic sclerosis/Myositis

Disease activity index for Systemic sclerosis designed by the Scleroderma Clinical Trials Consortium (SCTC).

Till date, there is no validated damage index for systemic sclerosis. The Scleroderma Clinical Trials Consortium (SCTC) attempted to design an index based on a 3-step process. First, the experts of the SCTC (n=331) scored on a list of potential items for inclusion in the DI. Items with >60% consensus were retained — next univariate analysis between these items and end-points of mortality and morbidity in the Australian cohort. In the third step, multivariate analysis was carried out to determine a weighted score.

Of 83 potential items, 22 were statistically significant after univariate analysis. One additional item forced into the multivariable model by experts due to clinical importance, to create a 23-item weighted SCTC DI (SCTC-DI). The SCTC-DI was predictive of morbidity and mortality in the validation cohort of Canadian SSc patients.

Ferdowsi N, Huq M, Stevens W, Hudson M, Wang M, Tay T, Burchell JL, Scleroderma Clinical Trials Consortium Damage Index Working Group, The Australian Scleroderma Interest Group, Canadian Scleroderma Research Group; Scleroderma Clinical Trials Consortium Damage Index Working Group, The Australian Scleroderma Interest Group, Canadian Scleroderma Research Group.  Development and validation of the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI): a novel instrument to quantify organ damage in systemic sclerosis. Ann Rheum Dis. 2019 Mar 30. pii: annrheumdis-2018-214764.

Near infra-red spectroscopy ( NIRS): a new tool to assess vascular perfusion in scleroderma

Optical Near-InfraRed Spectroscopy (NIRS) of blood HbO2 saturation (stO2) can evaluate O2 delivery/consumption balance in the explored tissue. NIRS-2D imaging is a simple, automated tool that can non-invasively detect regional microcirculatory impairment in SSc, which can add significant functional information to the morphological picture of nailfold-videocapillaroscopy. In the study by L Gargani et al(18)  ,a significant difference was found between controls and SSc patients in basal stO2 (84.3 ± 7.5 vs. 75.4 ± 10.9%, p < 0.001), minimum stO2 (65.2 ± 8.0 vs. 53.4 ± 10.1%, p < 0.001) and time to maximum stO2 during hyperemia (63 ± 38 vs. 85 ± 49 s, p < 0.05).

Gargani L, Bruni C, Barskova T, Hartwig V, Marinelli M, Trivella MG, et al. Near-infrared spectroscopic imaging of the whole hand: A new tool to assess tissue perfusion and peripheral microcirculation in scleroderma. Semin Arthritis Rheum. 2019;48(5):867–73.

Implication of ANCA positivity in Systemic sclerosis

A certain percentage of systemic sclerosis patients are known to have ANCA positivity, but its implication was unknown till date. Moxey et al collected data from 1303 patients from 5 centers in the Australian Scleroderma Cohort Study and found that 8.9% were ANCA positive. A significantly higher prevalence of interstitial lung disease (ILD) was found in the ANCA positive (44.8% vs 21.8%) and the anti-PR3 positive groups (50.0% vs 23.4%). Pulmonary embolism (PE) was also more common in ANCA-positive patients (8.6% vs 3.0%) and anti-PR3-positive patients (16.7% vs 3.3%). So they concluded that ANCA is associated with increased prevalence of ILD and PE in SSc.

Jayne Moxey, Molla Huq, Susanna Proudman, Significance of anti-neutrophil cytoplasmic antibodies in systemic sclerosisArthritis Research & Therapy201921:57 https://doi.org/10.1186/s13075-019-1839-5

SLE

A. October 2018 - January 2019

Presentation

A multi-centric study recorded initial clinical feature at the time of presentation in patients with early SLE, comparing them to patients with SLE mimicking conditions. Unexplained fever, autoimmune hemolysis and presence of Anti dsDNA, Direct Coomb’s test and low complement were more common in SLE, while Raynaud’s and sicca at presentation were more common in mimics. This study has bearings in deciding which criteria to include in classification and diagnostic criteria.

CNS Lupus

Annual assessments from a large SLE cohort of 1800 individuals for a median period of 7.5 years showed 31 events of psychosis in 28 (1.5%) patients. Earlier onset of disease, male sex, and African American ancestry were predictors of psychosis. Despite being featured prominently in the classification criteria, this follow up study shows that psychosis is actually quite uncommon in SLE.

Fracture Risk

Prospective records of nearly 50,000 SLE patients from Medicaid databases showed that SLE had an Hazard ratio of 2.09 in developing fratures (pelvis, wrist, hip, humerus). The highest risk was in patients with lupus nephritis (HR 3). Even adjusted for steroids, fracture risks remained high- which may be because of inflammation and muscle deconditioning.

IL2 therapy in SLE (and other autoimmune disease)

It is well known that IL2 activates and expands T regulatory cells. A pilot phase I-II study in mild to moderate SLE, RA, Sjogren’s and other autoimmune diseases were given IL2 (1 million IU per day). T regulatory expansion was observed in all, suggesting potential clinical efficacy. There were no major adverse effects. This early study demonstrates the safety of IL2 as a proof of concept.

References

B. February - April 2019

No difference between azathioprine and mycophenolate as maintenance therapy in lupus nephritis: meta-analysis of RCTs

In a meta-analysis of 7 RCTs looking at maintenance therapy for lupus nephritis, there were no statistical differences between patients on AZA or MMF in regards to mortality, relapse, ESRD, doubling of serum creatinine, infection, or gastrointestinal upset. In terms of adverse effects the MMF group incurred lower risks of leukopenia (RR = 0.16, 95% CI = 0.06 - 0.40; p = 0.0001) and amenorrhea (RR = 0.23, 95% CI = 0.09 - 0.59, p = 0.002) compared with the AZA group.

Deng J, Xie H, Zhu L, Luo L, Xie H. Maintenance therapy for lupus nephritis with mycophenolate mofetil or azathioprine. A meta-analysis. Clin Nephrol. 2019 Mar;91(3):172-179. doi: 10.5414/CN109450.

SLE-DAS: new tool on the block for lupus disease activity assessment

To develop a better tool for disease activity measurement in lupus overcoming the shortcomings of SLEDAI, SLE-DAS has been developed and validated by Diogo Jesus et al. SLE-DAS has 17 items and was derived and validated on 2 European cohorts consisting a total of 520 patients. The SLE-DAS provides more accurate identification of clinically meaningful changes over time, with much higher sensitivity as compared with SLEDAI-2K and similar specificity

SLE-DAS was highly correlated with PGA (r=0.875, p<0.0005) and SLEDAI-2K (r=0.943, p<0.0005) in the validation cohort. The optimal discriminative ΔSLE-DAS cut-off to detect a clinically meaningful change was 1.72. In the validation cohort, SLE-DAS showed a higher sensitivity than SLEDAI-2K (change ≥4) to detect a clinically meaningful improvement (89.5% vs 47.4%, p=0.008) or worsening (95.5% vs 59.1%, p=0.008), while maintaining similar specificities.

Jesus D, Matos A, Henriques C, Zen M, Larosa M, Iaccarino L, et al. Derivation and validation of the SLE Disease Activity Score (SLE-DAS): a new SLE continuous measure with high sensitivity for changes in disease activity. Ann Rheum Dis. 2019 Mar;78(3):365–71.

Risk models for Lupus Nephritis patients to assess adverse kidney outcomes

Another group of investigators has developed a series of working risk models that help in predicting relevant long‐term kidney outcomes in LN using patient response data after one year of therapy from a  database of 944 patients with LN assembled from 3 clinical trials and 12 longitudinal cohorts(12). The models need further validation in the clinical trial setting, and once validated, they can be used to standardize the reporting of trial results.

Mackay M, Dall'Era M, Fishbein J, Kalunian K, Lesser M, Sanchez-Guerrero J et al., Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials: Development and Validation of a Novel Approach to Predict Future Kidney Outcomes. Arthritis Rheumatol. 2019 Mar;71(3):411-419.

Belimumab is protective for organ damage in Lupus

In a study by MB Urowitz et al it was shown that organ damage progression was significantly lesser in patients with lupus who received belimumab in the BLISS long-term extension study (n=195) compared to with patients (propensity score matched) treated with standard of care from the Toronto Lupus Cohort (n=372).

Urowitz MB, Ohsfeldt RL, Wielage RC, Kelton KA, Asukai Y, Ramachandran S. Organ damage in patients treated with belimumab versus standard of care: a propensity score-matched comparative analysis. Ann Rheum Dis. 2019 Mar;78(3):372–9.

Mortality trends in ESRD due to LN

Mortality trends in 20,974 end-stage renal disease patients due to lupus nephritis was looked into by A Jorge et al from 1995 -2014 in US nationwide registry(14). The mortality rate per 100 patient‐years declined from 11.1 (95% confidence interval [95% CI] 10.4–11.8) in 1995–1999 to 6.7 (95% CI 6.2–7.2) in 2010–2014 (P for trend < 0.01). It was also observed in the study that there was a considerable reduction in all‐cause mortality among whites, African American and Hispanic patients, with  44% and 63% reduced risk of death from CVD and infection.

Jorge A, Wallace ZS, Zhang Y, Lu N, Costenbader KH, Choi HK. All-Cause and Cause-Specific Mortality Trends of End-Stage Renal Disease Due to Lupus Nephritis From 1995 to 2014. Arthritis Rheumatol. 2019 Mar;71(3):403-410.

Complications that develop in patients with congenital heart block, born to anti-SSA/Ro mothers and their siblings later in life

This is a fascinating study done by a Swedish group, led by Johannes Mofors et al 9, to collect information on comorbidity and complications that develop later in life in patients with congenital heart block born to anti-SSA/Ro mothers and their siblings. Data from patients with CHB (n= 119) and their siblings (n= 128), all born to anti-Ro/SSA-positive mothers, and from matched healthy controls (n= 1,190) and their siblings (n= 1,071), were retrieved from the Swedish National Patient Register. Individuals with CHB had a significantly increased risk of cardiovascular comorbidity, with cardiomyopathy and/or heart failure observed in 16.8% patients versus 0.3% controls, yielding an HR of 70.0 and with an HR for cerebral infarction of 39.9. Pacemaker treatment was associated with a decreased risk of cerebral infarction but increased risks of cardiomyopathy/heart failure and infection. Patients with CHB also had a higher risk of infections. Pacemaker treatment was associated with a decreased risk of cerebral infarction but increased risks of cardiomyopathy/heart failure and infection. The risk of systemic connective tissue disorder was also increased in patients with CHB (HR 11.8), and both patients with CHB and their siblings had an increased risk to develop any of 15 common autoimmune conditions (HR 5.7 and 3.6 respectively). This data thus indicates an increased risk of several cardiovascular, infectious and autoimmune diseases in patients with CHB, with the latter risk shared by their siblings.

Mofors J, Eliasson H, Ambrosi A, et al Comorbidity and long-term outcome in patients with congenital heart block and their siblings exposed to Ro/SSA autoantibodies in utero Annals of the Rheumatic Diseases Published Online First: 26 February 2019. doi: 10.1136/annrheumdis-2018-214406

List of DIL causing drugs from VigiBase

Drug-induced lupus (DIL) is an idiosyncratic side effect of treatments in which symptoms overlap with those of systemic lupus erythematosus (SLE). In this study, Arnaud et al. used the VigiBase, the WHO global individual case safety reports (ICSRs) database, to identify the main drugs associated with DIL. The drugs considered in the analysis were those not used to treat SLE, with a positive lower end of the 95% credibility interval for the information component (IC025) ≥0, an indicator value for disproportionate Bayesian reporting. This study enables the identification of 118 drugs associated with drug-induced lupus, among which 42 have not been previously reported as linked. The list of suspected drugs may prove useful to physicians when confronted with potential DIL cases.

Arnaud L, Mertz P, Gavand P, et al Drug-induced systemic lupus: revisiting the ever-changing spectrum of the disease using the WHO pharmacovigilance database Annals of the Rheumatic Diseases Published Online First: 04 February 2019. doi:10.1136/annrheumdis-2018-214598

Relationship between choroidopathy and lupus nephritis

Choroidopathy is a rare manifestation of systemic lupus erythematosus (SLE). This entity is associated with active phases of severe SLE and it is frequently accompanied by acute kidney failure, central nervous system involvement and coagulopathy. Braga et al, assessed the choroidal thickness by optical coherence tomography of 15 SLE patients with lupus nephritis in remission and compared it with that of 15 SLE patients without lupus nephritis in remission and 15 healthy controls. It was found that the choroidal thickness of lupus nephritis patients was significantly more than that of SLE patients without lupus nephritis and healthy controls, suggesting a relationship between the presence of lupus nephritis and choroidopathy.

Braga J, Rothwell R, Oliveira M, Rodrigues D, Fonseca S, Varandas R, Ribeiro L. Choroid thickness profile in patients with lupus nephritis. Lupus. 2019 Apr;28(4):475-482.

Prepregnancy hypertension and overweight are also determinants of pregnancy outcomes in patients

Pregnancies in women with lupus nephritis are at high-risk of complications. Normand et al. retrospectively reviewed medical charts of pregnancies that lasted more than 22 weeks in 66 patients with pre-existing lupus nephritis between 2004 and 2013 in France. A total of eighty-four pregnancies were identified. A maternal complication occurred in 36.9% of patients, mostly pre-eclampsia and renal flares. Overall fetal survival was 94.0%. Maternal age, prepregnancy hypertension, body mass index >25 kg/m2, and lupus immunological activity may be considered as the main determinants for fetal and maternal complications.

Normand G, Sens F, Puthet J, Jourde-Chiche N, Lemoine S, Chauveau D, Moranne O, Rémy P, Doret M, Daugas E, Juillard L; French Collaborative Group on Lupus Nephritis. Not only disease activity but also chronic hypertension and overweight are determinants of pregnancy outcomes in patients with systemic lupus erythematosus. Lupus. 2019 Apr;28(4):529-537.

Peripheral nerve involvement in SLE

Bortoluzzi et al. studied the profile of peripheral nerve involvement in SLE. The records of 1224 systemic lupus erythematosus patients examined at two tertiary referral centres over 14 years (from 2000 to 2014) were analyzed. The overall prevalence of peripheral nervous system involvement was 6.9%. Polyneuropathy was the most common manifestation (39.2%), followed by cranial neuropathy (30.9%) and single (12.4%) or multiple (8.2%) mononeuritis. Patients with peripheral nerve involvement were more likely to have higher SLE age at onset, higher SLEDAI-2K, SLICC/ACR Damage Index score, hypertension, and livedo reticularis. 

Bortoluzzi A, Piga M, Silvagni E, Chessa E, Mathieu A, Govoni M. Peripheralnervous system involvement in systemic lupus erythematosus: a retrospective study on prevalence, associated factors and outcome. Lupus. 2019. Apr;28(4):465-474.

Protective role of anti-Ribosomal-P in Lupus nephritis

This study focused on defining the clinical and histopathologic associations of anti-P positivity in Korean patients with biopsy-proven lupus nephritis. Seventy-nine patients were studied, out of which 35.4% were anti-P positive. Such patients exhibited earlier LN onset, a higher Systemic Lupus Erythematosus Disease Activity Index 2000 score, and a higher estimated glomerular filtration rate at the time of renal biopsy, than did those without antibodies. Upon renal histopathological analysis, patients with anti‐P exhibited less interstitial inflammation in terms of the activity index, less glomerular sclerosis, less tubular atrophy, and less interstitial fibrosis in terms of the chronicity index. At a median follow‐up time of 47 months, renal function was preserved in 27 of 28 patients who had anti‐P. After multivariate logistic regression, we found that anti‐P positivity was associated with a reduced rate of progression to chronic kidney disease. After multivariate logistic regression, we found that anti‐P positivity was associated with a reduced rate of progression to chronic kidney disease. So, the authors concluded that Anti‐P was associated with better histological findings, and anti‐P‐positive patients had better renal outcomes than those without anti‐P.

Kang JH, Park DJ, Choi SE, Yim YR, Kim JE, Lee JW, Lee KE, Kim TJ, Park YW,Lee JS, Choi YD, Lee JK, Lee SS. Protective role of anti-ribosomal P antibody in patients with lupus nephritis. Int J Rheum Dis. 2019 May;22(5):913-920.

Good outcomes with TNFi in refractory poor aPL related obstetric outcome

This studyaimed to assess the effectiveness of TNF-α blockers in 18 aPL-positive women with recurrent infertility after therapy with low-molecular-weight heparin (LMWH) plus aspirin (LDA) plus hydroxychloroquine (HCQ). Twelve women fulfilled the Sydney criteria for obstetric antiphospholipid syndrome (OAPS) and 6 had incomplete forms (OMAPS). All women tested positive for aPL at least twice. Sixteen patients were started on adalimumab and 2 on certolizumab. Twelve women completed gestation: 9 at term and 3 pre-term. First-trimester miscarriage or implantation failure recurred in 6 cases, all of the OAPS group. So, overall, good obstetric results were obtained in 70% of previous LMWH-LDA+HCQ refractory cases, and TNFi may thus be a promising treatment for refractory obstetric complaints related to aPL. 

 Jaume Alijotas-Reig, Enrique Esteve-Valverde, Elisa Llurba, Josep Mª Gris,Treatment of refractory poor aPL-related obstetric outcomes with TNF-alpha blockers: Maternal-fetal outcomes in a series of 18 cases, Seminars in Arthritis and Rheumatism, 2019, https://doi.org/10.1016/j.semarthrit.2019.02.006

Osteoarthritis

A. February - July 2019

Use of tramadol is associated with higher mortality at 1 year:

Most guidelines recommend tramadol as first-line therapy for osteoarthritis. In a epidemiological study in the United States all-cause mortality at one-year was compared in patients above 50 years with osteoarthritis between those prescribed tramadol  (n = 44 451) or one of five other drugs: naproxen (n = 12 397), diclofenac (n = 6512), celecoxib (n = 5674), etoricoxib (n = 2946), or codeine (n = 16 922). Propensity score matching was performed to match for covariates like age, comorbidities, etc.

Mortality with tramadol was higher than with Naproxen hazard ratio (HR- 1.71 [95% CI, 1.41-2.07]); diclofenac (HR- 1.88 [95% CI, 1.51-2.35]); celecoxib (HR- 1.70 [95% CI, 1.33-2.17]) and etoricoxib (HR- 2.04 [95% CI, 1.37-3.03]). There was no difference between tramadol and codeine (HR, 0.94 [95% CI, 0.83-1.05]). This again raises the question that has been plaguing rheumatologists for centuries: how to treat OA after all?

Zeng C, Dubreuil M, LaRochelle MR, Lu N, Wei J, Choi HK, Lei G, Zhang Y, Association of Tramadol With All-Cause Mortality Among Patients With Osteoarthritis. JAMA. 2019 Mar 12;321(10):969-982. doi: 10.1001/jama.2019.1347

Paracetamol versus placebo for knee and hip osteoarthritis

Given the above dilemma, I have just included one study from February since it comes from the Cochrane database, the Holy Grail of evidence for clinical medicine! In a massive meta-analysis (as the Cochrane reviews generally are), the authors identified 10 RCTs with paracetamol being compared against placebo. The paracetamol dose varied from 1.95 g/day to 4 g/day, and the majority of trials followed participants for three months only. There was unclear risks of selection bias in most studies.

Mean reduction in pain was 23 points (0 to 100 scale, lower scores indicated less pain) with placebo and 3.23 points better (5.43 better to 1.02 better) with paracetamol, an absolute reduction of 3% (1% better to 5% better, minimal clinical important difference 9%) and relative reduction of 5% (2% better to 8% better) (seven trials, 2355 participants). Thus paracetamol provides only minimal improvements in pain and function for people with hip or knee osteoarthritis, with no increased risk of adverse events overall. Subgroup analysis indicates that the effects on pain and function do not differ according to the dose of paracetamol.

Due to the small number of events, it could not be ascertained if paracetamol use increases the risk of serious adverse events, withdrawals due to adverse events, and the rate of abnormal liver function tests.

Leopoldino AO, Machado GC, Ferreira PH, Pinheiro MB, Day R, McLachlan AJ, Hunter DJ, Ferreira ML, Paracetamol versus placebo for knee and hip osteoarthritis. Cochrane Database Syst Rev. 2019 Feb 25;2: CD013273. doi: 10.1002/14651858.CD013273.

Lutikizumab and OA
In a Phase IIa study the efficacy, safety, pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1α/β dual variable domain immunoglobulin lutikizumab (ABT-981) in erosive hand osteoarthritis (HOA) was evaluated in 132 patients. Primary efficacy end-point of AUSCAN pain was not different among subjects treated with lutikizumab versus placebo at week 16. Other clinical and imaging endpoints were not different between lutikizumab and placebo. Lutikizumab significantly decreased serum high-sensitivity C reactive protein levels, IL-1α and IL-1β levels, and blood neutrophils. Lutikizumab pharmacokinetics were consistent with phase I studies and not affected by antidrug antibodies. Injection site reactions and neutropenia were more common in the lutikizumab group; discontinuations because of adverse events occurred more frequently with lutikizumab versus placebo

Kloppenburg M, Peterfy C, Haugen IK, Kroon F, Chen S, Wang L, et al. Phase IIa, placebo-controlled, randomised study of lutikizumab, an anti-interleukin-1α, and anti-interleukin-1β dual variable domain immunoglobulin, in patients with erosive hand osteoarthritis. Ann Rheum Dis. 2019 Mar;78(3):413–20.

Effusion- synovitis and infrapatellar fat pad signal intensity as predictors of accelerated knee OA

JE Davis et al studied 125 subjects with no radiographic Knee OA at the time of baseline and observed them for 2 years before and after recruitment. These patients were then divided into three groups a) Common OA b) Accelerated OA  and C) No radiographic OA at the end of observation period based on their progression.  In these subjects, the MRI findings were studied for predictors of progression and found that infrapatellar fat pad signal intensity alteration and large effusion-synovitis in a knee without radiographic OA predicts accelerated knee OA.

Davis JE, Ward RJ, MacKay JW, Lu B, Price LL, McAlindon TE, Eaton CB, Barbe

MF, Lo GH, Harkey MS, Driban JB. Effusion-synovitis and infrapatellar fat pad signal intensity alteration differentiate accelerated knee osteoarthritis. Rheumatology (Oxford). 2018 Oct 20.

Exploration of CRISPR/Cas9-based gene editing as therapy for osteoarthritis

Osteoarthritis (OA) is associated with aberrant upregulation of multiple factors, including matrix metalloproteinase 13 (MMP13), interleukin-1β (IL-1β) and nerve growth factor (NGF). In this study, authors aimed to use the CRISPR/Cas9 technology, a highly efficient gene-editing tool, to study whether the ablation of OA-associated genes has OA-modifying effects. They performed intra-articular injection of adeno-associated virus, which expressed CRISPR/Cas9 components to target each of the genes encoding MMP13, IL-1β and NGF, in a surgically induced OA mouse model. We also tested triple ablations of NGF, MMP13 and IL-1β. CRISPR-mediated ablation of NGF alleviates OA pain, and deletion of MMP13-1β or IL-1β attenuates structural damage in a post-traumatic OA model. Multiplex ablations of NGF, MMP13 and IL-1β provide benefits on both pain management and joint structure maintenance. Our results suggest that CRISPR-based gene editing is useful for the identification of promising drug targets and the development of feasible therapeutic strategies for OA treatment.

Zhao L, Huang J, Fan Y, Li J, You T, He S, et al. Exploration of CRISPR/Cas9-based gene editing as therapy for osteoarthritis. Annals of the Rheumatic Diseases [Internet]. 2019 Mar 6;78(5):676–82. Available from: http://dx.doi.org/10.1136/annrheumdis-2018-214724

Efficacy and safety of intra-articular injection of tropomyosin receptor kinase A inhibitor in painful knee osteoarthritis

This trial evaluated the efficacy and safety of GZ389988A, a tropomyosin receptor kinase A (TrkA) inhibitor, in subjects with painful knee osteoarthritis (OA). In this single center, double-blind, placebo-controlled and randomized trial, 104 subjects with moderate-to-severe knee OA pain were enrolled to receive a single intra-articular (IA) injection of either GZ389988A or placebo. Among weekly assessments, statistically significant greater improvement in the GZ389988A group was observed in WOMAC A1, overall knee pain and/or WOMAC A at weeks 2-5. Although not statistically significant, improvements over placebo on pain and WOMAC C persisted over 12 weeks. So, IA injection of TrkA inhibitor GZ389988A in knee OA subjects reduced pain with a numerically functional gain and an acceptable safety profile.

Krupka E, Jiang G-L, Jan C. Efficacy and safety of intra-articular injection of tropomyosin receptor kinase A inhibitor in painful knee osteoarthritis: a randomized, double-blind and placebo-controlled study. Osteoarthritis and Cartilage [Internet]. 2019 Jul; Available from: http://dx.doi.org/10.1016/j.joca.2019.05.028

Yoga for Osteoarthritis

This study aimed to systematically review and summarise the efficacy and safety of yoga for osteoarthritis. Medline (through PubMed), Scopus, and the Cochrane Library were searched through April 2018 for randomised controlled trials of yoga for osteoarthritis. Nine trials including 640 individuals with mainly lower extremity osteoarthritis aged 50-80 years were identified, with 80.3% female participants (median). Meta-analyses revealed very low-quality evidence for the effects of yoga on pain (vs. exercise: standardised mean difference (SMD) = - 1.07; 95%CI - 1.92, -  0.21; p = 0.01; vs. non-exercise: SMD = - 0.75; 95%CI - 1.18, - 0.31; p < 0.001), physical function (vs. exercise: SMD = 0.80; 95%CI 0.36; 1.24; p < 0.001; vs. non-exercise: SMD = 0.60; 95%CI 0.30, 0.98; p < 0.001), and stiffness (vs. exercise: SMD = - 0.92; 95%CI - 1.69, - 0.14; p = 0.008; vs. non-exercise: SMD = - 0.76; 95%CI - 1.26, - 0.26; p = 0.003) in individuals with knee osteoarthritis. Effects were not robust against potential methodological bias. No effects were found for quality of life, and depression, or for hand osteoarthritis. Safety was rarely reported. The findings of this meta-analysis indicate that yoga may be effective for improving pain, function, and stiffness in individuals with osteoarthritis of the knee, compared to exercise and non-exercise control groups. Due to the low methodological quality and potential risk of bias, only a weak recommendation can be made at this time for the use of yoga in adults with osteoarthritis of the knee.

Lauche R, Hunter DJ, Adams J, Cramer H. Yoga for Osteoarthritis: a Systematic Review and Meta-analysis. Current Rheumatology Reports [Internet]. 2019 Jul 23;21(9). Available from: http://dx.doi.org/10.1007/s11926-019-0846-5

Effectiveness of Denervation Therapy on Pain and Joint Function for Patients with Refractory Knee Osteoarthritis

Recently, denervation therapy has been applied clinically for the treatment of intractable osteoarthritis (OA). This therapy provides an alternative for patients who are insensitive to conservative therapies or unwilling to receive surgery and general anesthesia. In terms of postoperative pain intensity, denervation therapy showed significantly better short-term (4, 12, and 24 weeks) pain relief. The rates of 50% pain relief at 12 and 24 weeks after operation were also higher compared with the control group. In terms of joint functional improvement, denervation therapy showed favorable outcomes at 4 and 12 weeks after treatment, but no significant difference was found at 24 weeks after procedure between the groups. Overall, better results were reported in denervation therapy with a relative high-grade of evidence.

Denervation of the knee joint may become a promising therapy for patients with knee OA who are refractory to conservative treatment. This therapy can provide short-term therapeutic effect in pain alleviation for 6 months and joint function recovery for 3 months. The therapeutic effect in joint function may decrease 6 months after operation. The long-term efficacy in pain remission and function improvement is still elusive and controversial; therefore, further research with larger sample sizes are needed in the future.

Wang R, Ma C, Han Y, Tan M, Lu L. Effectiveness of Denervation Therapy on Pain and Joint Function for Patients with Refractory Knee Osteoarthritis: A Systematic Review and Meta-Analysis. Pain Physician. 2019;22(4):341-352.

Psoriatic Arthritis

A. October 2018 - January 2019

To assess the performance of sonographic elemental entheseal lesions in distinguishing between psoriatic arthritis (PsA) and controls for the development of sonographic score, the GRAPPA Ultrasound Working Group23 reported 5 elementary lesions (enthesophytes, Doppler signal, erosions, thickening, and hypoechogenicity) and 6 entheseal sites (patellar ligament insertions into the distal patella and tibial tuberosity,Achilles tendon and plantar fascia insertions into the calcaneus, common extensor tendon insertion into lateral epicondyle, and supraspinatus insertion into the superior facet of the humerus) that can contribute to development of new scoring system.

On Comparing different remission and low disease definitions in Psoriatic Arthritis and Evaluating their prognostic value, Laura C et al reported VLDA and MDA definitions to be more stringent than DAPSA and cDAPSA definitions for the assessment of PsA.24

In the study by Kim Wervers et al25 to assess the HRQOL in patients newly diagnosed with PsA, it was found that HRQOL was diminished in PsA at time of diagnosis compared to the Dutch reference population, and tender joints, enthesitis at clinical examination, and back pain as indicators of pain affected HRQOL.

In the 2 year results from phase III FUTURE 2 study it was reported that Secukinumab-treated patients achieved higher PASDAS-defined remissions or LDA compared with placebo at week 16, which were sustained through 2 years.26

A randomised, placebo-controlled, phase 2 trial (EQUATOR) found Filgotinib to be efficacious and safe for the treatment of active psoriatic arthritis.27

In the study of patient reported outcomes in abatacept treated PsA patients from Phase 3 trial, it was reported that abatacept treatment improved PROs in patients with PsA versus placebo, with better results in elevated baseline CRP and TNFi-naïve subpopulations.28

In the integrated analysis of two phase 3 randomized trials in psoriatic arthritis by Dafna D et al, data from SPIRIT-P1 and SPIRIT-P2 was used. Among patients with pre-existing enthesitis or dactylitis, Ixekizumab (IXEQ2W-2 week and IXEQ4W-4 week) treatment resulted in significant improvements in enthesitis and dactylitis. Enthesitis resolution was associated with improvements in patients’ function, pain, and HRQoL.29

BioTRAC is an ongoing, prospective registry of inflammatory arthritis patients. 188 PsA patients treated with golimumab were included to calculate the proportion of patients achieving different clinical criteria (MDA/DAPSA), their prognostic value and the overall patient impact of these disease states, very low disease activity was the most stringent new potential target for remission in PsA. There was a high level of agreement between different scores. Patients achieving DAPSA endpoint, however, did not show a significant reduction in skin disease, indicating that the criteria was more restricted to joint symptoms.30

In a pooled analysis of 21 clinical trials31 that reported the incidence rates of inflammatory bowel disease (IBD) in patients receiving treatment with secukinumab for psoriasis (PsO), psoriatic arthritis (PsA) or ankylosing spondylitis (AS),A total of 7355 patients with a cumulative exposure of 16 226.9 PY were included. Among 5181 patients with PsO, there were 14 cases of UC, 5 cases of CD and 1 case of IBDU, with exposure adjusted incidence rates (EAIRs) of 0.13, 0.05 and 0.01, respectively. Of these 20 cases, 14 were new-onset. In 1380 patients with PsA, there were 3 cases of UC, 3 cases of CD and 2 cases of IBDU (EAIRs 0.08, 0.08 and 0.05); 7 of these represented new-onset cases. Among 794 patients with AS, there were 4 cases of UC, 8 cases of CD and 1 case of IBDU (EAIRs 0.2, 0.4 and 0.1); 9 were new-onset cases. In the per year analysis, the EAIRs for each indication did not increase over time with secukinumab treatment.

B. February - April 2019

Prevalence of minimal disease activity in Australian patients with Psoriatic Arthritis: Assessing the outcome of national funding criteria for biologic disease‐modifying antirheumatic drug prescribing.

The prevalence of minimal disease activity (MDA) achievement and differences in inflammatory marker levels between PsA patients who have and have not met the Australian Pharmaceutical Benefits Scheme (PBS) criteria for bDMARDs were studied. Minimal disease activity was achieved by 56/105 participants overall. There were no differences in inflammatory marker levels or involved joint count patterns between the PsA and RA groups at the time of bDMARD qualification. Seventy‐three percent of the 53 PsA patients on bDMARD achieved MDA, vs 33% in the non‐bDMARD group (P < 0.001). More bDMARD than non‐bDMARD patients achieved four out of seven MDA components. Of those with any enthesitis, its prevalence was higher in the non‐bDMARD group (22 vs 10, P = 0.009). Regardless of treatment, there was no difference in inflammatory marker levels between those who did and did not achieve MDA.

Pontifex, EK, Dissanayake, K, Bursill, D, Gill, T.  Prevalence of minimal disease activity in Australian patients with Psoriatic Arthritis: Assessing the outcome of national funding criteria for biologic disease‐modifying antirheumatic drug prescribing. Int J Rheum Dis.  2019; 22: 262– 268. https://doi.org/10.1111/1756-185X.13441

Polyarticular evolution and late‐onset psoriasis may be associated with cardiovascular disease in psoriatic arthritis. 

Cross‐sectional study of 340 consecutive patients seen in a tertiary care hospital was undertaken to correlate PsA and cardiovascular risk factors (CVRF). The prevalence of CVRF was compared to that of 600 outpatients without inflammatory conditions. Patients with psoriatic arthritis had higher frequencies of hypertension (36% vs 23%, OR 2.4, 95%CI: 1.6‐2.7, P < 0.0001), diabetes (13.8% vs 5%, OR 2.8, 95%CI: 1.7‐4.3, P < 0.0001), obesity (35% vs 22%, OR 2.1, 95%CI: 1.5‐2.8, P < 0.0001) and tobacco use (26% vs 21%, OR 1.4, 95%CI: 1.0‐1.8, P < 0.05). More PsA patients had CVD compared to non‐inflammatory patients (9.4% vs 5.8%, OR 1.68, 95%CI: 1.02‐2.76, P < 0.05). Independent CVD‐associated factors were: an age of onset of psoriasis >40 years (OR 3.4, 95%CI: 1.1‐10.0, P < 0.05), a high number of swollen joints during evolution (OR 2.9, 95%CI: 1.1‐8.0, P < 0.05), hypertension (OR 5.3, 95%CI: 1.6‐17.6, P < 0.01) and dyslipidemia (OR 2.6, 95%CI: 1.0‐7.2, P < 0.05).

Queiro, R,  Lorenzo, A,  Tejón, P,  Pardo, E,  Coto, P,  Ballina, J.  Polyarticular evolution and late‐onset psoriasis may be associated with cardiovascular disease in psoriatic arthritis. Int J Rheum Dis.  2019; 22: 269– 274. https://doi.org/10.1111/1756-185X.13421

Effect of Achieving Minimal Disease Activity on the Progression of Subclinical Atherosclerosis and Arterial Stiffness: A Prospective Cohort Study in Psoriatic Arthritis

A total of 101 consecutive patients with PsA were recruited for this prospective cohort study. All patients received treatment targeting MDA for a period of 2 years according to protocol. High‐resolution carotid ultrasound and arterial stiffness markers were assessed annually. The primary outcome measure was the effect of achieving MDA at 12 months (MDA group) on the progression of subclinical atherosclerosis over 24 months. Secondary objectives were to compare the changes in arterial stiffness markers over 24 months between the MDA and non‐MDA groups, as well as the changes in subclinical atherosclerosis and arterial stiffness markers in patients who achieved MDA at each visit from month 12 through month 24 (sustained MDA [sMDA]). Ninety PsA patients (mean ± SD age 50 ± 11 years, 58% male [n = 52]) who completed 24 months of follow‐up were included in this analysis. Fifty‐seven patients (63%) had achieved MDA at 12 months. Subclinical atherosclerosis and arterial stiffness outcomes were similar between the MDA and non‐MDA groups. Forty‐one patients (46%) achieved sMDA. As shown by multivariate analysis, achieving sMDA had a protective effect on plaque progression (odds ratio 0.273 [95% confidence interval 0.088–0.846], P = 0.024), and less of an increase in total plaque area, mean intima‐media thickness, and augmentation index values after adjustment for covariates.

Cheng, I. T., Shang, Q. , Li, E. K., Wong, P. C., Kun, E. W., Law, M. Y., Yip, R. M., Yim, I. C., Lai, B. T., Ying, S. K., Kwok, K. Y., Li, M. , Li, T. K., Zhu, T. Y., Lee, J. J., Chang, M. M., Szeto, C. , Yan, B. P., Lee, A. P. and Tam, L. (2019), Effect of Achieving Minimal Disease Activity on the Progression of Subclinical Atherosclerosis and Arterial Stiffness: A Prospective Cohort Study in Psoriatic Arthritis. Arthritis Rheumatol, 71: 271-280. doi:10.1002/art.40695

Validation of new potential targets for remission and low disease activity in psoriatic arthritis in patients treated with golimumab

New potential targets for remission and low disease activity in psoriatic arthritis in patients treated with golimumab were validated. BioTRAC is an ongoing, prospective registry of inflammatory arthritis patients. 188 PsA patients treated with golimumab were included. Data collected at baseline, 6 and 12 months were used. Between 15.6% and 38.3% of patients achieved remission, and 37.4–77.7% achieved low disease activity at 6 and 12 months’ follow-up. Patients achieving any minimal disease activity target and DAPSA low disease activity had significantly lower swollen joint count, tender joint count, psoriasis area and severity index, dactylitis and enthesitis scores compared with non-achievers (P < 0.05). Higher HAQ scores (P < 0.03) were observed in patients achieving remission with remaining dactylitis or active skin disease. Very low disease activity was the most stringent new potential target for remission in PsA. There was a high level of agreement between scores, although residual activity in dactylitis and skin despite DAPSA remission may affect patient function. Patients achieving either DAPSA endpoint, however, did not show a significant reduction in skin disease, indicating that those two criteria are more restricted to joint symptoms.

Laura C Coates, Proton Rahman, Eliofotisti Psaradellis, Emmanouil Rampakakis, Brendan Osborne, Allen J Lehman, Francois Nantel, Validation of new potential targets for remission and low disease activity in psoriatic arthritis in patients treated with golimumab, Rheumatology, Volume 58, Issue 3, March 2019, Pages 522–526, https://doi.org/10.1093/rheumatology/key359

Psoriatic arthritis screening: a systematic review and meta-analysis

A systematic review of MEDLINE, Excerpta Medical Database, Cochrane Central Register of Controlled Trials and Web of Science was conducted to identify studies that evaluated the accuracy of self-administered PsA screening tools for patients with psoriasis. A bivariate meta-analysis was used to pool screening tool-specific accuracy estimates (sensitivity and specificity). Heterogeneity of the diagnostic odds ratio was evaluated through meta-regression.A total of 2280 references were identified and 130 records were assessed for full-text review, of which 42 were included for synthesis. Of these, 27 were included in quantitative syntheses. Of the records, 37% had an overall low risk of bias. Fourteen different screening tools and 104 separate accuracy estimates were identified. Pooled sensitivity and specificity estimates were calculated for the Psoriatic Arthritis Screening and Evaluation (cut-off = 44), Psoriatic Arthritis Screening and Evaluation (47), Toronto Psoriatic Arthritis Screening (8), Psoriasis Epidemiology Screening Tool (3) and Early Psoriatic Arthritis Screening Questionnaire (3). The Early Psoriatic Arthritis Screening Questionnaire reported the highest sensitivity and specificity (0.85 each). The I2 for the diagnostic odds ratios varied between 76 and 90.1%. Meta-regressions were conducted, in which the age, risk of bias for patient selection and the screening tool accounted for some of the observed heterogeneity.Questionnaire-based tools have moderate accuracy to identify PsA among psoriasis patients. The Early Psoriatic Arthritis Screening Questionnaire appears to have slightly better accuracy compared with the Toronto Psoriatic Arthritis Screening, Psoriasis Epidemiology Screening Tool and Psoriatic Arthritis Screening and Evaluation. An economic evaluation could model the uncertainty and estimate the cost-effectiveness of PsA screening programs that use different tools.

Nicolas Iragorri, Glen Hazlewood, Braden Manns, Vishva Danthurebandara, Eldon Spackman, Psoriatic arthritis screening: a systematic review and meta-analysis, Rheumatology, Volume 58, Issue 4, April 2019, Pages 692–707, https://doi.org/10.1093/rheumatology/key314

Impact of High‐Intensity Interval Training on Disease Activity and Disease in Patients With Psoriatic Arthritis: A Randomized Controlled Trial

67 patients with PsA (43 women and 24 men) were randomly assigned to an intervention group in which patients performed HIIT for 11 weeks or a control group of patients who were instructed not to change their physical exercise habits. Outcomes were assessed at 3 months and 9 months with the patient's global assessment (PGA), fatigue, and pain scores measured on a 100‐mm visual analog scale (VAS), and the composite Disease Activity Score in 44 joints (DAS44) was calculated. We used linear mixed models to calculate the mean difference (95% confidence interval [95% CI]) between groups according to the intent‐to‐treat principle. At 3 months, there was no clear difference in the PGA score (–0.49 [95% CI –10.91, 9.94]), DAS44 (–0.08 [95% CI –0.36, 0.20]), or pain intensity (5.45 [95% CI –4.36, 15.26]) between the groups. However, patients in the intervention group reported less fatigue (–12.83 [95% CI –25.88, 0.23]) than those in the control group. There was no evidence of long‐term effects of HIIT on outcomes measured at 9 months. Thus the patients with PsA tolerate HIIT without deterioration of disease activity and with improvement in fatigue.

Thomsen, R. S., Nilsen, T. I., Haugeberg, G., Bye, A., Kavanaugh, A. and Hoff, M. (2019), Impact of High‐Intensity Interval Training on Disease Activity and Disease in Patients With Psoriatic Arthritis: A Randomized Controlled Trial. Arthritis Care Res, 71: 530-537. doi:10.1002/acr.23614

Regression of Peripheral Subclinical Enthesopathy in Therapy‐Naive Patients Treated With Ustekinumab for Moderate‐to‐Severe Chronic Plaque Psoriasis: A Fifty‐Two–Week, Prospective, Open‐Label Feasibility Study

Seventy‐three patients with moderate‐to‐severe psoriasis, who were not treated with systemic therapy and did not have symptoms of psoriatic arthritis (PsA), and 23 healthy volunteers were screened by ultrasound for subclinical enthesitis. Subsequently, 23 patients with psoriasis whose ultrasound results showed inflammatory changes were treated with ustekinumab for 52 weeks. The evolution of sonographic abnormalities of the upper and lower limb entheses was assessed using an extensive gray‐scale and power Doppler (PD) ultrasound protocol at weeks 0, 12, 24, and 52. For each parameter, a gray‐scale or PD ultrasound score of >0 was determined to be abnormal, and a summative score based on the Glasgow Ultrasound Enthesitis Scoring System was calculated. Of all the patients with psoriasis screened using ultrasound, 49.3% had at least one inflammatory entheseal abnormality. Mean ± SD inflammation scores were higher in the patients with psoriasis compared with the healthy volunteers (9.9 ± 6.6 versus 1.0 ± 1.4). With treatment, the mean inflammation scores decreased significantly by 42.2% from week 0 to week 24 (–4.2 [95% confidence interval –6.3, –2.1]; P< 0.001) and by 47.5% by week 42 (–4.7 [95% confidence interval –7.1, –2.3]; P = 0.001). Entheseal structural abnormalities did not change significantly during treatment.

Savage, L. , Goodfield, M. , Horton, L. , Watad, A. , Hensor, E. , Emery, P. , Wakefield, R. , Wittmann, M. and McGonagle, D. (2019), Regression of Peripheral Subclinical Enthesopathy in Therapy‐Naive Patients Treated With Ustekinumab for Moderate‐to‐Severe Chronic Plaque Psoriasis: A Fifty‐Two–Week, Prospective, Open‐Label Feasibility Study. Arthritis Rheumatol, 71: 626-631. doi:10.1002/art.40778

Drug levels of Adalimumab correlate with disease activity in axial SpA

In a single-center study, 51 patients with AxSpA on adalimumab were assessed for drug levels and anti-drug antibodies. Median adalimumab (mg/l) was significantly higher in patients with inactive disease/low disease activity. Patients with inactive disease/low disease activity presented significantly lower levels of anti-drug antibodies. Serum adalimumab levels above 4.6 mg/l were recommended to avoid compromising efficacy.

Another significant finding was that patients on concomitant methotrexate had lower levels of anti-drug antibodies. This may be a case for use of MTX along with adalimumab in AxSpA.

Senabre Gallego JM, Rosas J, Marco-Mingot M, García-Gómez JA, Santos-Soler G, Salas-Heredia E, Pons-Bas A, Barber-Vallés X, Bernal-Vidal JA, Cano-Pérez C, García-Carrasco M, Flores-Pardo E; AIRE-MB Group. Clinical relevance of monitoring serum adalimumab levels in axial spondyloarthritis. Rheumatol Int. 2019 Mar 21. doi: 10.1007/s00296-019-04288-7. [Epub ahead of print]

If HLA-B27 status is known, family history may as well be skipped!!

Across three cohorts (the Assessment of Spondyloarthritis international Society (ASAS), DEvenir des Spondyloarthropathies Indifférenciéés Récentes (DESIR) and SPondyloArthritis Caught Early (SPACE) cohorts ASAS n = 594, DESIR n = 647, and SPACE n = 577), 1818 patients suspected of axSpA were analysed for significance of positive family history. HLA-B27 was independently associated with an axSpA diagnosis in each cohort but an ASAS definition of positive family history was not. [ASAS cohort: HLA-B27 odds ratio (OR): 6.9 (95% CI: 4.7, 10.2), ASAS-PFH OR: 0.9 (95% CI: 0.6, 1.4); DESIR: HLA-B27 OR: 2.1 (95% CI: 1.5, 2.9), ASAS-PFH OR: 1.0 (95% CI 0.7, 1.3); SPACE: HLA-B27 OR: 10.4 (95% CI: 6.9, 15.7), ASAS-PFH OR: 1.0 (95% CI: 0.7, 1.5)]. Similar negative results were found for PFH of AS and acute anterior uveitis.

This indicates that in the vast majority of patients presenting with back pain, a PFH does not contribute to the likelihood of an axSpA diagnosis if HLA-B27 status is known.

van Lunteren M, van der Heijde D, Sepriano A, Berg IJ, Dougados M, Gossec L, Jacobsson L, Ramonda R, Rudwaleit M, Sieper J, Landewé R, van Gaalen FA. Is a positive family history of spondyloarthritis relevant for diagnosing axial spondyloarthritis once HLA-B27 status is known? Rheumatology (Oxford). 2019 Apr 1. pii: kez095. doi: 10.1093/rheumatology/kez095. [Epub ahead of print]

Is there a role of estimating anti-CD74 antibodies in suspect AxSpA? Evidence from a cohort with low HLA-B27 prevalence.

The middle-east has a low prevalence of HLA-B27. In such a region from Lebanon, the clinical utility of anti-CD74 antibodies was evaluated. Diagnostic properties were calculated (sensitivity, specificity, positive, and positive predictive values (PPV, NPV), Likelihood ratios) consider physician diagnosis and ASAS imaging criteria as a gold standard. Forty-nine axSpA patients and 102 blood donors were included in the final analysis.

IgA anti-CD74 correlated poorly with axSpA (Area Under the Curve (AUC) 0.657), whereas IgG4 anti-CD74 had a good discriminative value (AUC 0.837). Respectively, for HLA-B27, IgG4 anti-CD74, and the combination of both, the sensitivity was 33-92-33%, and specificity was 96-79-98%. Thus IgG4 anti-CD74 antibodies combined with HLA-B27 showed higher diagnostic value than HLA-B27 alone for early axSpA in such regions.

Ziade NR, Mallak I, Merheb G, Ghorra P, Baerlecken N, Witte T, Baraliakos X. Added Value of Anti-CD74 Autoantibodies in Axial SpondyloArthritis in a Population With Low HLA-B27 Prevalence. Front Immunol. 2019 Mar 26;10:574. doi: 10.3389/fimmu.2019.00574. eCollection 2019.

Sjogren's Syndrome

A. February - April 2019

Sjogren’s and Dementia

In a 12-year, nationwide, population-based, retrospective cohort study in Taiwan(10), the risk of dementia in patients of Sjogren's syndrome was assessed. The incidence of dementia in this cohort was 1.21-fold that in the control cohort (95% confidence interval [CI] = 1.02–1.45, p < 0.05). In the group older than 65years, the incidence of dementia was significantly high (adjusted hazard ratio [aHR] = 5.30, 95% CI = 4.26–6.60, p < 0.01).

Chen H-H, Perng W-T, Chiou J-Y, Wang Y-H, Huang J-Y, Wei JC-C. Risk of dementia among patients with Sjogren’s syndrome: A nationwide population-based cohort study in Taiwan. Semin Arthritis Rheum. 2019;48(5):895–9.

Infections in Rheumatology

A. February - April 2019

Neutrophil CD64 expression and serum TREM-1 can distinguish disease flare from infection in lupus and ANCA associated vasculitis

The role of CD64 expression on neutrophils has been previously explored in ICU studies to identify bacterial infections. In rheumatology when a patient with diagnosed CTD or vasculitis presents with fever, there is always a dilemma if it is due to disease flare or some infection. Ajmani and associate report that neutrophil CD64 can help solve this dilemma!

For patients with bacterial infection (n = 25), active disease (n = 51), and healthy controls (n = 20), Neutrophil CD64 expression using flow cytometry and sTREM-1 and procalcitonin levels by ELISA were estimated. )). The sensitivity and specificity of CD64 expression on neutrophils to diagnose bacterial infection (using a cutoff value of 30%) was 85% and 84%, respectively, as compared to the sensitivity and specificity of procalcitonin (75% and 85%, respectively). Serum TREM-1 did not show significant differences between the groups.

Ajmani S, Singh H, Chaturvedi S, Mishra R, Rai MK, Jain A, Misra DP, Agarwal V. Utility of neutrophil CD64 and serum TREM-1 in distinguishing bacterial infection from disease flare in SLE and ANCA-associated vasculitis. Clin Rheumatol. 2019 Apr;38(4):997-1005. doi: 10.1007/s10067-018-4334-5.

IgG4 Related Disease

A. February - April 2019

Distinct disease phenotypes in IgG4 RD

Investigators for ACR/EULAR IgG4-RD Classification Criteria Committee published their findingson Clinical phenotypes of IgG4-related disease based on their retrospective analysis of two international cross-sectional cohorts.They identified in the derivation cohort (n=493), four groups with distinct manifestations: Group 1 (31%), Pancreato-Hepato-Biliary disease; Group 2 (24%), Retroperitoneal Fibrosis and/or Aortitis; Group 3 (24%), Head and Neck-Limited disease and Group 4 (22%), classic Mikulicz syndrome with systemic involvement, which was also mirrored in the replication cohort. They also found that being Asian ethnicity or female may predispose individuals to head and neck-limited disease of IgG4 related disease spectrum.

Wallace ZS, Zhang Y, Perugino CA, Naden R, Choi HK, Stone JH, et al. Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts. Ann Rheum Dis. 2019 Mar;78(3):406–12.

Tissue eosinophilia and Serum IgE: surrogate markers for IgG4 related RPF

In a Chinese study (23)on 50 patients with retroperitoneal fibrosis, the researchers found that IgG4 related RPF patients had high serum IgE concentration and tissue eosinophilia in comparison to idiopathic RPF. The level of serum IgE was strongly correlated with that of IgG4 in retroperitoneal fibrosis patients.

Liao S, Zhang X, Zhu F, Wang Y, Zhu J, Zhang J, Huang F. Comparison of two subsets of Chinese patients with retroperitoneal fibrosis in terms of IgG4 immunohistochemical staining. Rheumatology (Oxford). 2018 Nov 21.

IgG4: IgG RNA ratio may be a new disease activity marker in GPA.

An important limitation in granulomatosis with polyangiitis (GPA) is the lack of disease activity markers. A Al Soudi et al in a cross-sectional study included 35 GPA patients. Active disease was defined as Birmingham Vasculitis Activity Score (BVAS) ≥ 3 (n = 15), remission as BVAS of 0 (n = 17), and low disease activity (LDA) as BVAS of 1–2 and clinical remission (n = 3). Using a validated qPCR test, they measured the IgG4: IgG RNA ratio in all groups and compared the results with known biomarkers. The median qPCR score was higher in active GPA (21.4; IQR 12.1–29.6) than in remission/LDA and correlated well with BVAS. A cutoff qPCR score of 11.2% differentiated active disease from remission/LDA accurately. So, this group highlighted that the IgG4: IgG RNA ratio might be a new disease activity marker in GPA.

Al-Soudi, M. E. Doorenspleet, R. E. Esveldt et al. IgG4:IgG RNA ratio differentiates active disease from remission in granulomatosis with polyangiitis: a new disease activity marker? A cross-sectional and longitudinal study Arthritis Research & Therapy201921:43 https://doi.org/10.1186/s13075-018-1806-6

Gout

A. February - April 2019

USEFUL STUDY

Investigators of USEFUL study(26) performed a 6-month multicentre prospective study on 79 patients USG proven gout and looked into whether USG could help to monitor response to urate lower therapy in these patients and its correlation with serum uric acid levels. In this study, they observed that ultrasonography can show decreased urate deposition in the joints after urate-lowering therapy and is correlated with decreased serum urate level. Hence ultrasonography can be useful for gout follow-up and checking adherence to urate-lowering therapy.

Ebstein E, Forien M, Norkuviene E, Richette P, Mouterde G, Daien C, Ea HK, Brière C, Lioté F, Petraitis M, Bardin T, Ora J, Dieudé P, Ottaviani S. Ultrasound evaluation in follow-up of urate-lowering therapy in gout: the USEFUL study. Rheumatology (Oxford). 2018 Oct 4. doi: 10.1093/rheumatology/key303. 

Romidepsin, a dual HDAC inhibitor, maybe a new treatment option in acute gout

MCP Cleophas et al has explored a new treatment option to limit inflammation in acute gout: specific histone deacetylase (HDAC) inhibition. Peripheral blood mononuclear cells (PBMCs) were cultured with a combination of monosodium urate crystals (MSU) and palmitic acid (C16.0) to activate the NLRP3 inflammasome and induce IL-1β production. HDAC inhibitors and other compounds were added beforehand with a 1-h pre-incubation period. The HDAC1/2 inhibitor romidepsin was most potent in lowering C16.0+MSU-induced IL-1β production compared to other specific class I HDAC inhibitors. Romidepsin also increased SOCS1 expression and blocked STAT1 and STAT3 activation. It was also found that blocking the proteasome (with Bortezomib) could reverse the cytokine suppression by romidepsin. So, these results showed that romidepsin (HDAC1/2 dual inhibitor) is a very potent inhibitor of C16.0+MSU-induced cytokines in vitro.

M. C. P. Cleophas, T. O. Crişan, V. Klück. Romidepsin suppresses monosodium urate crystal-induced cytokine production through upregulation of suppressor of cytokine signaling one expression. Arthritis Research & Therapy201921:50 https://doi.org/10.1186/s13075-019-1834-x

Serum Bisphenol A is an independent risk factor of hyperuricemia: A 6-year prospective study

Bisphenol A (BPA) is an environmental endocrine disruptor that is typically used in food containers, so human exposure to BPA is widespread. Recent studies in animals and cells indicated that BPA might promote hyperuricemia via activating xanthine oxidase, hence it may be a risk factor of hyperuricemia, but uncertainty prevails. In this study, Jinbo Hu et al. enrolled 482 participants without hyperuricemia at baseline and followed up for six years. After six years of follow-up, the change in serum uric acid concentration from baseline to the 6-year mark was significantly higher in subjects with higher baseline BPA concentration. Multivariable logistic analyses showed that subjects in the median or high baseline BPA tertiles exhibited a twofold higher risk of 6-year hyperuricemia incidence compared to subjects in the low baseline BPA tertile. In conclusion, serum BPA is an independent risk factor for hyperuricemia.

Jinbo Hu, Chuan Peng, Jiayu Li, Serum Bisphenol A is an independent risk factor of hyperuricemia: A 6-year prospective study, Seminars in Arthritis and Rheumatism,Volume 48, Issue 4, 2019, Pages 644-648, https://doi.org/10.1016/j.semarthrit.2018.03.009

Fibromyalgia

A. February - April 2019

Small fiber neuropathy in fibromyalgia

A systematic review and meta-analysisof the prevalence of small fiber pathology in fibromyalgia were performed by R Grayston et al.full-text articles which satisfied the inclusion criteria and were assessed for a total of 222 participants. The meta-analysis demonstrated the pooled prevalence of small fiber pathology in fibromyalgia was 49% (95% CI: 38–60%) with a moderate degree of heterogeneity, (I2= 68%). This new link in etiopathogenesis might provide a basis for future therapeutics in fibromyalgia.

Grayston R, Czanner G, Elhadd K, Goebel A, Frank B, Üçeyler N, et al. A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: Implications for a new paradigm in fibromyalgia etiopathogenesis. Semin Arthritis Rheum. 2019;48(5):933–40.

Miscellaneous

A. February - April 2019

IMMUNE CHECK INHIBITOR (ICI) RELATED RHEUMATOLOGICAL MANIFESTATIONS

Large single-center cohort of ICI related rheumatic manifestations

A database of 1,293 patients who received any ICI at the Mayo Clinic Rochester, Minnesota campus between 2011 -2018, were retrospectively studied for Rh‐irAEs which was clinically diagnosed in 61  patients . Clinical syndromes included inflammatory arthritis (n = 34 [prevalence 2%]), myopathy (n = 10), and other rheumatic syndromes (n = 17). Inflammatory arthritis was most commonly polyarticular, and glucocorticoid treatment was required in 26 patients (76%). Five patients (15%) also received disease‐modifying antirheumatic drugs, and ICI therapy had to be discontinued in 3 patients (9%). Myopathy was treated with glucocorticoids in all cases and led to 2 deaths and permanent ICI discontinuation in 9 patients (90%). Other syndromes included connective tissue diseases, vasculitis, polymyalgia rheumatica–like syndrome, and flare of preexisting rheumatic disease. Most (71%) were treated with immunosuppression, with 12% requiring ICI discontinuation.

Richter MD, Crowson C, Kottschade LA, Finnes HD, Markovic SN, Thanarajasingam U. Rheumatic Syndromes Associated With Immune Checkpoint Inhibitors: A Single-Center Cohort of Sixty-One Patients. Arthritis Rheumatol. 2019 Mar;71(3):468-475.

Cluster analysis of autoimmune diseases based on autoantibodies

Classification of autoimmune diseases is based on phenotypic expression. Molano-González and associates attempted to re-classify these diseases based on autoantibody profiles. They included 187 consecutive women with established systemic lupus erythematosus (n = 70), rheumatoid arthritis (n = 51), systemic sclerosis (n = 35) and Sjögren's syndrome (n = 31). Six clusters were obtained, built mainly on autoantibodies: PolyA-I to -VI. The PolyA-III cluster showed the highest frequency of overt PolyA (p = 0.01), and the PolyA-I, -III, and -IV clusters exhibited the highest positivity for IL-12/23p40 (p = 0.015). These results provide new insights into the pathophysiology of autoimmune diseases. Further studies would be required, including systems biology and clinical features for cluster analysis to identify new disease entities which we might be forcing into preconceived disease categories!

Molano-González N, Rojas M, Monsalve DM, Pacheco Y, Acosta-Ampudia Y, Rodríguez Y, Rodríguez-Jimenez M, Ramírez-Santana C, Anaya JM. Cluster analysis of autoimmune rheumatic diseases based on autoantibodies. New insights for polyautoimmunity. J Autoimmun. 2019 Mar;98:24-32. doi: 10.1016/j.jaut.2018.11.002. Epub 2018 Nov 17.