Rheumatology International

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Boxplots of serum matrix metalloproteinase 3 (panel a) and myeloperoxidase (panel b) across the study groups. **p < 0.001
Boxplots of synovial fluid matrix metalloproteinase 3 (panel a) and synovial fluid myeloperoxidase (panel b) in psoriatic arthritis patients with and without crystals versus gonarthrosis patients with no crystals. *p < 0.05; ***p < 0.001
Research on biomarkers for the diagnosis and monitoring of psoriatic arthritis (PsA) is ongoing. The purpose of this study was to assess the potential of serum and synovial fluid matrix metalloproteinase-3 (MMP-3) and myeloperoxidase (MPO) as biomarkers for PsA and their relation to disease activity indices. This case–control study involved 156 psoriatic arthritis patients, 50 gonarthrosis patients, and 30 healthy controls. The target parameters were measured with the enzyme-linked immunosorbent assay (ELISA) kits. Serum MMP-3 and MPO levels were elevated in the PsA patients in comparison to the two control groups (p < 0.001) and distinguished PsA from GoA patients and healthy controls with 100% accuracy. Synovial MMP-3 discriminated PsA from GoA patients irrespective of the presence of crystals (AUC = 1.00). PsA patients with crystals in the synovial fluid had elevated synovial MPO (p < 0.001) and were distinguished from PsA patients without crystals with accuracy of 88.50% and from GoA patients with accuracy of 88.30%. Synovial fluid MPO was positively associated with the following indicators of disease activity: VAS (rs = 0.396); DAPSA (rs = 0.365); mCPDAI (rs = 0.323). Synovial MMP-3 showed a weaker positive association with DAPSA (rs = 0.202) and mCPDAI (rs = 0.223). Our results suggest that serum MMP-3 and MPO could serve as biomarkers for PsA. Synovial fluid MMP-3 showed a potential as a biomarker for PsA versus GoA. Synovial MPO could be utilized as a marker for the presence of crystals in PsA patients.
Flowchart of the bibliographic search strategy and selection criteria. ANCA anti-neutrophil cytoplasmic antibodies, COVID-19 coronavirus disease 2019, RT-PCR reverse transcription polymerase chain reaction, SARS-CoV-2 severe acute respiratory syndrome coronavirus-2
COVID-19 has been related to several autoimmune diseases, triggering the appearance of autoantibodies and endothelial dysfunction. Current evidence has drawn attention to vasculitis-like phenomena and leukocytoclastic vasculitis in some COVID-19 patients. Moreover, it has been hypothesized that COVID-19 could induce flares of preexisting autoimmune disorders. Here, we present two patients with previously controlled IgA vasculitis who developed a renal and cutaneous flare of vasculitis after mild COVID-19, one of them with new-onset ANCA vasculitis. These patients were treated with glucocorticoids and immunosuppressants achieving successful response. We also provide a focused literature review and conclude that COVID-19 may be associated with triggering of vasculitis and could induce flares of previous autoimmune diseases.
The total number of attacks in each season: 40 in autumn, 57 in winter, 41 in spring, and 29 in summer. Chi-square goodness-of-fit test significance for equality: 0.023
Although it is assumed that cold exposure triggers inflammation in patients with familial Mediterranean fever (FMF), seasonal differences in FMF have not yet been investigated. This study aims to investigate the association of seasonal changes with the frequency of attacks, disease severity, and subclinical inflammation in FMF. This longitudinal study examined adult patients with FMF on an established treatment followed up for at least 1 year in Istanbul. Clinical characteristics, medications, intraseasonal attacks counts, arthralgia and arthritis, disease severity, and the subclinical inflammation parameters were recorded covering four seasons. Friedman’s and Cochran’s Q tests were used to analyze changes in the above-mentioned data over seasons. Additionally, all attacks experienced in each season were added, and interseasonal differences were compared with the Chi-square goodness-of-fit test. Data for 240 observations (60 patients) were analyzed. The mean age and disease duration were 39.78 (SD 11.91) and 10 (IQR 6–22.75) years, respectively. The comparison of medians for four seasons did not show any statistical differences in terms of attack frequency, disease severity parameters, markers of subclinical inflammation, and the presence of arthralgia and arthritis. The total number of intraseasonal attacks experienced by patients differed among the seasons (p = 0.023), with a higher count in winter. Adult individuals with established FMF are more likely to experience attacks in winter than summer, but this difference may not be seen in the general parameters of disease activity/severity. This result supports the notion that there is a pronounced residual activity in winter.
Anti-MDA5 (Melanoma differentiation-associated protein 5) myositis is a rare subtype of dermatomyositis (DM) characterized by distinct ulcerative, erythematous cutaneous lesions and a high risk of rapidly progressive interstitial lung disease (RP-ILD). It has been shown that SARS-CoV-2 (COVID-19) replicates rapidly in lung and skin epithelial cells, which is sensed by the cytosolic RNA-sensor MDA5. MDA5 then triggers type 1 interferon (IFN) production, and thus downstream inflammatory mediators (EMBO J 40(15):e107826, 2021); (J Virol, 2021, https://doi.org/10.1128/JVI.00862-21); (Cell Rep 34(2):108628, 2021); (Sci Rep 11(1):13638, 2021); (Trends Microbiol 27(1):75–85, 2019). It has also been shown that MDA5 is triggered by the mRNA COVID-19 vaccine with resultant activated dendritic cells (Nat Rev Immunol 21(4):195–197, 2021). Our literature review identified one reported case of MDA5-DM from the COVID-19 vaccine (Chest J, 2021, https://doi.org/10.1016/j.chest.2021.07.646). We present six additional cases of MDA5-DM that developed shortly after the administration of different kinds of COVID-19 vaccines. A review of other similar cases of myositis developing from the COVID-19 vaccine was also done. We aim to explore and discuss the evidence around recent speculations of a possible relation of MDA5-DM to COVID-19 infection and vaccine. The importance of vaccination during a worldwide pandemic should be maintained and our findings are not intended to discourage individuals from receiving the COVID-19 vaccine.
Skin ulcers with granulations, photo of the anterior (A) and (B) posterior surface of the left leg at presentation
The presence of clinical criteria for Behçet’s disease in the described clinical cases
Behçet's disease (BD) is a rare (especially in East Europe, Ukraine) systemic vasculitis of blood vessels of varying calibers throughout the body that affects various organs. The variability of the clinical features requires the involvement of doctors of different specialties in the management of such patients. The work was aimed to conduct a literature review of the intestine involvement and skin lesions in BD based on the clinical case with bloody diarrhea at the onset, and to assess the frequency of development of various clinical syndromes in intestinal BD. This is an attempt at describing a manifestation of BD with colitis and to emphasize the necessary revision of BD diagnostic criteria with special attention to early manifestations of BD with gastrointestinal tract involvement.
Frequency of post-COVID-19 symptoms in patients, n = 88
The prevalence of chronic EBV, HHV6 in the active phase in patients with the post-COVID condition
The prevalence of activated EBV and HHV6 infections depending on biological media
The global spread of SARS-CoV-2 points to unrivaled mutational variation of the virus, contributing to a variety of post-COVID sequelae in immunocompromised subjects and high mortality. Numerous studies have reported the reactivation of "sluggish" herpes virus infections in COVID-19, which exaggerate the course of the disease and complicate with lasting post-COVID manifestations CMV, EBV, HHV6). This study aimed to describe clinical and laboratory features of post-COVID manifestations accompanied by the reactivation of herpes virus infections (CMV, EBV, HHV6). 88 patients were recruited for this study, including subjects with reactivation of herpes viruses, 68 (72.3%) (main group) and 20 (27.7%) subjects without detectable DNA of herpesviruses (control group): 46 (52.3%) female and 42 (47.7%) male; median age was 41.4 ± 6.7 years. Patients with post-COVID manifestations presented with reactivation of EBV in 42.6%, HHV6 in 25.0%, and EBV plus HHV6 in 32.4%. Compared with controls, patients with herpes virus infections presented with more frequent slight fever temperature, headache, psycho-neurological disorders, pulmonary abnormalities and myalgia (p < 0.01), activation of liver enzymes, elevated CRP and D-dimer, and suppressed cellular immune response (p ≤ 0.05). Preliminary results indicate a likely involvement of reactivated herpes virus infections, primarily EBV infections in severe COVID-19 and the formation of the post-COVID syndrome. Patients with the post-COVID syndrome and reactivation of EBV and HHV6 infections are at high risk of developing various pathologies, including rheumatologic diseases.
To examine the association between common comorbidities, eGFR and loci involved in the hyperuricaemia-gout transition. This study was conducted in people with gout from the UK Biobank. Logistic regression was used to examine the association between self-reported physician-diagnosed hypertension, diabetes, hypercholesterolemia and ischaemic heart disease (IHD) with the following variants: rs1260326(GCKR), rs16890979(SLC2A9), rs2231142(ABCG2), rs1229984(ADH1B) and rs2078267(SLC22A11) and adjusted for age, sex and 10-principal components. Linear regression was used to examine the association with eGFR. 7,049 participants with gout were included. After adjusting for multiple testing, there was a statistically significant positive association between urate lowering allele at SLC2A9 and hypertension, and negative association between urate raising allele at ABCG2 and hypertension (OR 1.17 and OR 0.86, respectively). Number of urate lowering risk alleles associated with hypertension [OR (95%CI) 1.13 (1.06–1.21)]. High eGFR associated with urate raising allele at rs2231142 ( β = 1.38). The SNP in ADH1B that protects from alcohol excess showed a negative association with IHD (OR 0.53). Unlike in general population studies urate lowering genetic variants associate with hypertension in gout patients with dose–response. This may be due to high prevalence of other risk factors of hypertension such as obesity, poor diet etc. and needs validation in independent datasets.
Distribution of TNF-α levels in the groups of ACS patients with and without RA. **p < 0.01
Significant positive association of TNF-α expression with the serum biomarkers TNF-α 48 h. (a); IL-6 48 h. (b); hs-CRP 24 h. (c); hs-CRP 48 h. (d)
ROC curves show the level of accuracy of serum IL-6 (48 h), TNF-α (48 h), and hs-CRP (48 h) in distinguishing ACS patients with RA from ACS patients without RA
The role of inflammatory cytokines is well researched in acute coronary syndrome (ACS) and rheumatoid arthritis (RA), but not in the presence of both conditions. This study aimed to compare TNF-α expression, serum TNF-α, IL-6, and hs-CRP in ACS patients with RA (n = 46) with ACS patients without RA (n = 49) and healthy controls (n = 50). TNF-α expression was assessed from coronary artery samples, taken during coronary artery bypass surgery. Serum levels TNF-α, IL-6, and hs-CRP were measured 24 and 48 h after cardiac surgery. Stronger TNF-α expression was observed in the ACS patients with RA versus the ACS patients without RA, p = 0.001. Serum TNF-α, IL-6, and hs-CRP at the 24th h were significantly elevated in both patient groups and distinguished them from the healthy controls with accuracy ranging from 80 to 99%. At the 48th h, serum TNF-α and IL-6 in the ACS group without RA decreased to those of the healthy controls but remained high in the group with RA. ACS cases with RA could be correctly identified from the levels of IL-6 (AUC = 0.885, 95% CI 0.791 to 0.938) and TNF-α (AUC = 0.852, 95%CI 0.720 to 0.922). Our results suggest that the presence of RA in ACS cases is likely to provoke stronger TNF-α expression on atherosclerotic plaques, aggravate the pro-inflammatory response, and sustain it even after the cardiac stress is lowered. In ACS cases with RA, long-term monitoring and control of TNF-α and IL-6 levels can be a useful preventive strategy.
Behçet’s disease (BD) is a systemic vasculitis of unknown etiology causing recurrent mucocutaneous lesions, ocular involvement, central nervous system involvement, and vascular involvement. The disease is characterized by exacerbations and spontaneous remissions. Prognosis is poor in young men when the vessels are involved. The course is more active and severe in the first years of the disease. One of the most interesting features of BD is that the disease changes to a state of low activity and remission over time. Although the association between aging and lower disease activity is well established, there is limited literature data and research investigating the cause. Similarly, there are not many studies on the late onset of BD and its characteristics. In this regard, understanding the cause of the decline in disease activity over time may open new avenues for pathogenesis and treatment research. In this review, we focus on the immunosenescence caused by chronic inflammation and aging in BD. Based on the effect of testosterone on innate immune cells, we also briefly discussed the potential effects of this hormone on vascular involvement.
Study cohort selection
Kaplan–Meier estimates of the time to the first occurrence of the composite primary end point (hospitalization due to angina pectoris, nonfatal myocardial infarction, nonfatal subarachnoid or cerebral hemorrhage, nonfatal ischemic stroke, or death from any cause)
Patients with hyperuricemia and gout are at an increased risk for cardiovascular (CV) disease. Inhibition of the xanthine oxidase with allopurinol or febuxostat have become the mainstay for urate lowering therapy. However, it has been suggested that febuxostat increases the risk for CV mortality as compared to allopurinol. The aim of this retrospective cohort study was to assess the CV risk among patients with febuxostat or allopurinol therapy. Patients who initiated urate lowering therapy with febuxostat or allopurinol between 2014 and 2017 were selected from the drug reimbursement database of the Austrian health insurances funds. The primary CV endpoint was a composite of angina pectoris, nonfatal myocardial infarction, nonfatal subarachnoid or cerebral hemorrhage, nonfatal ischemic stroke, or death from any cause. In total, 28.068 patients (62.1% male) with a mean age of 71 years were included. 7.767 initiated febuxostat treatment and 20.301 received allopurinol. The incidence rate per 100 patient-years of the composite primary endpoint was 448 (febuxostat) and 356 (allopurinol) with a corresponding adjusted hazard ratio (HR) of 0.58 (95% CI 0.53–0.63) for allopurinol vs. febuxostat initiators. Similar HR were found for secondary endpoints including all-cause mortality [0.61 (95% CI 0.55–0.68)] and separate analyses of cardiac events [0.48 (95% CI 0.38–0.61)] and ischemic stroke [0.47 (95% CI 0.36–0.61)]. Data from this Austrian population-based study suggests that febuxostat initiators are at an increased risk for nonfatal CV events or death from any cause as compared to those with allopurinol. This is consistent with CV concerns of other trials, which limited the broad therapeutic use of febuxostat.
Elastographic image of a parotid gland in pSS group
ROC analysis of diagnostic accuracy of salivary gland elastography (mean of 4 salivary glands elastography results) in detection of primary Sjögren’s syndrome
The primary aim of this study was to verify if shear wave elastography can be used to evaluate salivary gland involvement in primary Sjögren's syndrome (pSS). The secondary objective was to establish an accurate cut-off value for parotid and submandibular salivary gland stiffness and to verify whether there are any distinctions among pSS patients with or without subjective mouth dryness. This prospective study included 45 patients with pSS (2016 ACR/EULAR classification criteria) and 108 healthy controls. All subjects underwent bilateral shear wave elastography of the parotid and submandibular salivary glands. Clinical data of pSS patients were collected and compared to elastography results. Patients with pSS had significantly higher shear wave elastography values for the parotid and submandibular salivary glands than the controls. There were no statistical differences in SWE values between patients with or without mouth dryness. The optimal cut-off value (mean value of 4 salivary glands shear wave elastography results) to distinguish patients with or without pSS was 13.19 kPa with sensitivity = 97.8% and specificity = 100.0%. It was, therefore, confirmed that shear wave elastography measurement of salivary glands has strong predictive ability in pSS detection (AUC 97.8%, 95% CI 93.4–100.0%). Shear wave elastography seems to be a promising, non-invasive and simple quantitative adjunct test to support the diagnosis of pSS with good sensitivity and specificity. More extensive prospective studies are needed to standardize a study protocol.
Molecular structure of approved anti-TNFs. The five approved anti-TNFs, presented in chronological order of first approval. Etanercept is a fusion protein of extracellular domain (p75) of human TNFR2 and Fc fragment of IgG1; infliximab is a mouse/human chimeric monoclonal IgG1 anti-TNF-α antibody; adalimumab is a humanized IgG1 monoclonal anti-TNF-α antibody; certolizumab is a Fc-free Fab region of a recombinant humanized IgG1 monoclonal anti-TNF-α antibody, conjugated to PEG; golimumab is a human IgG1 monoclonal anti-TNF-α antibody. Anti-TNF-a: tumor necrosis factor alpha inhibitor, PEG: polyethylene glycol, TNFR2: tumor necrosis factor receptor 2
Long-term beneficial effects of anti-TNFs. Beneficial effects of anti-TNFs in bones, joints, intestine and cardiovascular system. IBD: Inflammatory bowel disease
Since the late 1990s, tumor necrosis factor alpha (TNF-α) inhibitors (anti-TNFs) have revolutionized the therapy of immune-mediated inflammatory diseases (IMIDs) affecting the gut, joints, skin and eyes. Although the therapeutic armamentarium in IMIDs is being constantly expanded, anti-TNFs remain the cornerstone of their treatment. During the second decade of their application in clinical practice, a large body of additional knowledge has accumulated regarding various aspects of anti-TNF-α therapy, whereas new indications have been added. Recent experimental studies have shown that anti-TNFs exert their beneficial effects not only by restoring aberrant TNF-mediated immune mechanisms, but also by de-activating pathogenic fibroblast-like mesenchymal cells. Real-world data on millions of patients further confirmed the remarkable efficacy of anti-TNFs. It is now clear that anti-TNFs alter the physical course of inflammatory arthritis and inflammatory bowel disease, leading to inhibition of local and systemic bone loss and to a decline in the number of surgeries for disease-related complications, while anti-TNFs improve morbidity and mortality, acting beneficially also on cardiovascular comorbidities. On the other hand, no new safety signals emerged, whereas anti-TNF-α safety in pregnancy and amid the COVID-19 pandemic was confirmed. The use of biosimilars was associated with cost reductions making anti-TNFs more widely available. Moreover, the current implementation of the “treat-to-target” approach and treatment de-escalation strategies of IMIDs were based on anti-TNFs. An intensive search to discover biomarkers to optimize response to anti-TNF-α treatment is currently ongoing. Finally, selective targeting of TNF-α receptors, new forms of anti-TNFs and combinations with other agents, are being tested in clinical trials and will probably expand the spectrum of TNF-α inhibition as a therapeutic strategy for IMIDs.
Methodology for patient inclusion. FM Fibromyalgia, MTZ Mirtazapine, DLX Duloxetine
On the background of a restricted armamentarium of drugs available for the management of fibromyalgia (FM), we aimed to compare the real-world effectiveness of two serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine (MTZ) and duloxetine (DLX) in FM. A medical records review was done to identify patients diagnosed with FM and prescribed a stable dose of either MTZ or DLX for more than 6 months. Their present status was determined by a telephonic interview which included a subjective assessment of improvement (Likert scale), FIQR (Revised Fibromyalgia Impact Questionnaire), adverse drug effects and compliance. One-fifty-eight patients were screened to include 81 patients [mean age 46.7 (± 13.0) years, 64 (79%) females]. Sixty (79%) had primary fibromyalgia and 66 (81.5%) were on DLX (20–40 mg) while 15(18.5%) were on MTZ (7.5 mg). In addition to the drugs, lifestyle modification was followed by 57 (70.3%). A moderate-to-good improvement was seen in 66 (81.5%), while 15 (18.5%) reported poor to no improvement overall. In the DLX group, a majority (59, 89.4%) showed moderate-to-good improvement compared to 7(46.7%) on MTZ [p = 0.001, 9.6(2.6–34)]. However, FIQR was similar for those on DLX (3.6 ± 0.9) and MTZ (3.8 ± 0.7). Adverse effects were reported for 51 (77%) of patients on DLX and all (100%) on MTZ with a poorer compliance with MTZ 5 (33.3%) compared to DLX 47 (71.2%) [p = 0.008, OR 0.1(0.03–0.4)]. On multivariate analysis, DLX use [OR 16.7 (95% CI 2.7–100); p = 0.008] and lifestyle modification [p = 0.002; OR 11.2(1.5–83.3)] were associated with better subjective outcomes. Low-dose MTZ appears to be inferior to DLX in the management of FM in this real-world cohort.
We aimed to explore the efect of tofacitinib on erectile dysfunction (ED), as well as disease activity and health related quality of life in male patients with rheumatoid arthritis (RA). Forty eight male RA patients with ED were included. Demographic and clinical data at baseline and 6 month of treatment were recorded from patients’ medical records. Disease activity was evaluated with the disease activity score on 28 joints (DAS28), quality of life with Health Assessment Questionnaire—Disability Index (HAQ-DI) and ED with International Index of Erectile Function—5 (IIEF-5). The patients were aged 45.58 ± 2.14 years with a disease duration of 79.33 ± 25.31 months. According to the IIEF-5, 17 (35.4%) patients had severe ED, 10 (20.8%) patients moderate ED, 10 (20.8%) patients mild to moderate ED and 11 (22.9%) patients mild ED. For the entire patient group, baseline median IIEF-5 score was signifcantly increased from 9.35 (5.30–19.40) to 9.90 (5.20–24.90), baseline median DAS28 was signifcantly decreased from 5.65 (4.80–6.70) to 5.00 (2.40–6.40), HAQ-DI from 1.70 (1.10–2.40) to 1.15 (0.40–2.20) at 6th month of treatment (all p value<0.001). Also, quantitative change in IIEF-5 was signifcantly correlated with changes in DAS28 (r: − 0.735, p<0.001) and HAQ-DI (r: − 0.700, p<0.001). Tofacitinib monotherapy may improve ED severity and as well as disease activity and health related quality of life in male patients with RA complaining of ED.
Model shown to survey respondents depicting connection between reduced HRV and suboptimal therapeutic immunosuppression
Survey response flow chart
Percentage of rheumatologists agreeing with statements about autonomic nervous system (ANS) state and heart rate variability (HRV)
Percentage of rheumatologists who would consider using a test to measure the state of the autonomic nervous system (ANS) for specific groups of patients
The term “immuno-autonomics” has been coined to describe an emerging field evaluating the interaction between stress, autonomic nervous system (ANS), and inflammation. The field remains largely unknown among practicing rheumatologists. Our objective was to evaluate the perspectives of rheumatologists regarding the role of stress in the activity and management of rheumatoid arthritis (RA). A 31-item survey was conducted with 231 rheumatologists. Rheumatologists were asked to assess the role of stress in rheumatoid arthritis (RA) disease activity and were provided with information regarding immuno-autonomics. They were asked to consider how immuno-autonomics resonated with their patient management needs. The majority of rheumatologists are eager to better understand non-response, believe that stress biology and ANS dysfunction interfere with disease activity, and embrace the theory that measurement of ANS via next-generation HRV may be able to evaluate autonomic dysfunction and the biology of stress. Rheumatologists are open to the idea that quantitative measurement of ANS function using next-generation HRV can be a helpful tool to RA practice. The majority agree that ANS state influences RA disease control and that quantitative measures of ANS state are helpful to RA practice. Rheumatologists also agree that patients with poor ANS function may be at risk for not responding adequately to conventional, biologic, or targeted synthetic DMARDs. Almost all would use an in-office test to quantitatively measure ANS using next-generation HRV. This study shows that rheumatologists are open to embracing evaluation of ANS function as a possible tool in the management and treatment of RA.
Patient disposition during the study
This study aimed to evaluate the autonomic dysfunction as assessed by the Composite Autonomic Symptom Score-31 (COMPASS-31) as well as its relationship with disease activity and cardiovascular risks in patients with psoriatic arthritis (PsA). This cross-sectional observational study involved 118 PsA patients (85 females, mean age 45.6 years) and 64 healthy subjects. Cardiovascular risks were recorded including body mass index (BMI), hypertension (HT), diabetes mellitus (DM), dyslipidemia, metabolic syndrome (MetS), and 10-year Framingham Risk scores (FRS) were calculated. PsA was assessed with regard to disease activity, quality of life, and function. Autonomic dysfunction was evaluated using the COMPASS-31 consisting of six subdivisions including orthostatic, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor functions. The mean disease duration was 63.3 months. The mean total COMPASS-31 score was significantly higher in PsA patients than in controls (24.4 vs 11.1; p < 0.001), as were all sub-domain scores. COMPASS-31 scores were significantly lower in patients with DAPSA-REM and MDA. The COMPASS-31 total score showed significant correlations with scores of pain, global assessment, fatigue, function, quality of life, DAPSA, and BASDAI (p < 0.05).The presence of HT, dyslipidemia, MetS, and abdominal obesity did not significantly affect the total COMPASS-31 and sub-domain scores, except for the secretomotor scores being significantly higher in patients with abdominal obesity and MetS (p < 0.05). COMPASS-31 scores were not significantly different across the FRS risk groups. The symptoms of autonomic dysfunction are prevalent in PsA patients. High disease activity and pain have negative effects on autonomic function, and also functional impairment, fatigue, and poor quality of life are associated with autonomic dysfunction. However, the COMPASS-31 was found to be insufficient to demonstrate a clear relationship between autonomic dysfunction and cardiovascular risk.
HandScan. The HandScan (Demcon Hemics, The Netherlands) is a new imaging device for the detection of inflammation. Patients place both hands in the device simultaneously, resting on a plate. Red/near-infrared light illuminates the hand and the amount of light that passes through the hand is recorded by a camera. The more blood is present, the less light is passed through. The total procedure takes approximately 5–10 min and can be executed by any healthcare professional after a short training [15]. The HandScan produces a value for the level of inflammation for each separate joint and a combined score for the entire hand. The inflammation is also shown visually with a scale from green to red superimposed on the joints of the hand and wrists. This may help to understand the current activity of a patient’s arthritis as well as to localize inflammatory activity. Previous research showed that the HandScan is a sensitive and specific test with good validity [15, 16]. This makes it interesting to examine the HandScan as a potential addition to or (partial) replacement of current measures for inflammatory activity such as blood tests, DAS28, MRI, and ultrasound
To enable patients with rheumatoid arthritis (RA) and their healthcare professionals to choose the optimal treatment, it is crucial to accurately assess the current state of inflammatory activity. The objectives of this study were to (1) investigate the perspective of RA patients on their insight into the current status of their disease, and to (2) investigate the patients’ perspective on the possible added value of a monitoring device based on optical spectral transmission—called the HandScan—that measures the location and severity of joint inflammation. A survey was distributed online among patients with RA in the Netherlands. Four-hundred and eight patients with RA completed the survey. Of these, 298 (73%) felt they have sufficient insight into their current disease status. Most respondents perceived either a large (n = 242; 59%) or small (n = 148; 36%) added value of the HandScan in their monitoring process, mostly because the device provides additional knowledge on the presence of inflammation. This perceived added value was higher for respondents experienced with the device (n = 46; p = .04). Respondents preferred monitoring with the device on every (n = 192; 47%) or most (n = 171; 42%) visits to the outpatient clinic, or even more often than on every visit (n = 17; 4%). Monitoring RA using an optical spectral transmission device is seen by patients as a possibly valuable addition to the monitoring process of inflammatory activity during visits to an outpatient clinic. Their main reason was that the device can increase insight into their current disease status. More insight may support patients in discussing treatment options with their rheumatologist.
Standardised elastogram landmark and elasticity ratio measurement method for DPT [32]
An advanced ultrasound imaging technique, sonoelastography (SE) is used to evaluate tissue elasticity. To determine SE potential to detect pathological-related changes, and characteristics related to tendon pathology we aimed to (1) compare quadriceps and patellar tendon findings in individuals with knee osteoarthritis (KOA) and asymptomatic older adults (AC), and (2) explore associations between SE, participant characteristics (age, BMI, and leg circumference) and KOA status. 84 participants (47; KOA and 37; asymptomatic older adults) underwent SE examination of quadriceps (distal) and patellar (distal, proximal) tendon in a supine position with the knee bent at 30°. Colour score (CS) and Elasticity Ratio (ER) analysis were performed by a blinded experienced operator using Esaote Mylab 70 XVG Ultrasound equipment. Significantly reduced elasticity in the distal quadriceps (median (IQR) 2(2), 3(1), p = 0.033 for KOA and AC, respectively) and proximal patellar (3(1), 3(0), p = 0.001) tendons and more elastic distal patellar (1.50 (0.55), 1.87 (0.72), p = 0.034) tendons were observed in the KOA group. Significant associations) were identified between SE and participant BMI (Rs = − 0.249-0.750, p < 0.05) and leg circumference (Rs = − 0.260-0.903, p < 0.05). Age, BMI and KOA status, were independent explanatory variables of SE CS findings at the distal quadriceps tendon patellar tendon, proximal patellar tendon and distal patellar tendon, explaining 66%, 81% and 64% of variance, respectively. Age, BMI and KOA status were independent explanatory variables of SE ER findings at the distal patellar tendon explaining 19% of variance. Potentially clinically relevant altered tendon stiffness were observed between individuals with KOA and asymptomatic controls. Key KOA risk factors and participant characteristics explained variance in tendon stiffness. Findings provide context for future studies to investigate the potential for targeted SE detected early clinical management based on associated participant characteristics.
Vaccine hesitancy is considered a major barrier to achieving herd immunity against COVID-19. While multiple alternative and synergistic approaches including heterologous vaccination, booster doses, and antiviral drugs have been developed, equitable vaccine uptake remains the foremost strategy to manage pandemic. Although none of the currently approved vaccines are live-attenuated, several reports of disease flares, waning protection, and acute-onset syndromes have emerged as short-term adverse events after vaccination. Hence, scientific literature falls short when discussing potential long-term effects in vulnerable cohorts. The COVAD-2 survey follows on from the baseline COVAD-1 survey with the aim to collect patient-reported data on the long-term safety and tolerability of COVID-19 vaccines in immune modulation. The e-survey has been extensively pilot-tested and validated with translations into multiple languages. Anticipated results will help improve vaccination efforts and reduce the imminent risks of COVID-19 infection, especially in understudied vulnerable groups.
Peripheral blood smear showing schizocytes (magnification, 400 ×)
Renal pathological findings with Periodic acid Schiff stain (a) and Periodic acid methenamine silver stain (b) (magnification, 200 ×)
Clinical course after admission. Cr creatinine, CRP C-reactive protein, FFP fresh frozen plasma, GC glucocorticoid, Hb hemoglobin, HHQ hydroxychloroquine, IVMP intravenous pulses of methylprednisolone, MMF mycophenolate mofetil, PE plasma exchange, Plt platelet, RTX rituximab
Duration until administration of RTX is represented in the remission (n = 16) and non-remission groups (n = 3) (a) and in the alive (n = 14) and death groups (n = 5) (b). Dots show the data for individual cases. * p < 0.05, ** p < 0.01. RTX rituximab
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies and deposition of immune complexes on tissues. Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening hematological disorder that rarely develops in SLE, mainly caused by inhibitory or clearing autoantibody against ADAMTS13. Although B cells play critical roles in the pathogenesis of two diseases, the role of B-cell depletion therapy using rituximab (RTX), a chimeric monoclonal antibody targeting CD20, in the management of TTP associated with SLE remains unclear. We present a 27-year-old woman who manifested TTP and nephritis simultaneously at diagnosis of SLE. This patient successfully responded to high-dose glucocorticoids combined with plasma exchange, and early administration of RTX-induced sustained remission of TTP without relapse over 16 months. This literature review in light of our case demonstrates relationship between early intervention with RTX and better treatment response despite the degree of ADAMTS13 activity. Moreover, we discuss the clinical features in TTP associated with SLE, risk factors for the development of TTP in SLE, and possible outcomes based on RTX dose. It is important to consider upfront RTX as a promising treatment strategy for SLE-associated secondary TTP to improve short-term response and long-term prognosis.
This study aimed to investigate the frequency of CS and its clinical and functional effects on familial Mediterranean fever (FMF). A hundred FMF patients were included in this study. The presence of CS was investigated by the central sensitization inventory (CSI). In addition to the detailed clinical features of patients and genetic mutations, quality of life, disability, sleep disorders, depression, anxiety, and fibromyalgia frequency were examined to evaluate the negative effects of CS on the individual. Patients were divided into groups according to the presence and severity of CS, and their results were compared. Correlation and multivariate regression analysis were performed to investigate the association of CS with selected demographic and clinical parameters. The mean CSI was 37.72 (SD: 19.35), and thirty-eight (38%) patients had CS. Sacroiliitis occurred in 11 patients (11%), amyloidosis in 3 (3%), and erysipelas-like erythema in 11 (11%). The most prevalent genetic mutation was M694/any compound heterogeneous (35.7%), followed by M69V homogeneous (30%). Regarding comparing the patients with and without CS, the number of attacks, disease activity, daily colchicine dose, and all investigated comorbidities were significantly higher in the patients with CS (p < 0.05). In regression analysis, gender, colchicine dose and sleep disturbance were detected as related parameters with CS (OR (95% CI): 6.05 (1.39; 26.32), p: 0.017, OR (95% CI): 6.69 (1.65; 27.18), p: 0.008, OR (95% CI): 1.35 (1.35; 1.59), p: 0.001, respectively). Concomitant pain sensitization appears to be related to FMF patients' clinical and functional characteristics. These results suggest taking into consideration CS in the management of FMF patients.
Study flowchart
Time to first urinary incontinence episode shown against urinary continence status at admission and for the complete study-cohort. After a steep drop due to patients with UI at inclusion (dash), the curve shows a shallower decrease due to new UI episodes among patients continent of urine at study inclusion (long dash-dot). UI: urinary incontinence
Prevalence and types of urinary incontinence (UI) between first and second study visits (panel A) and between second and third study visits (panel B). Small boxes and arrows show the percentages of patients whose subtype of UI had changed. * Due to missing data, the sums of the proportions do not equal 100 per cent. UI: urinary incontinence
Prevalence and severity of urinary incontinence (UI) between first and second study visits (panel A) and between second and third study visits (panel B). Small boxes and arrows show the percentages of patients whose severity of UI had changed. * Due to missing data, the sums of the proportions do not equal 100 per cent. UI: urinary incontinence
Investigate the natural history of urinary incontinence (UI) in systemic sclerosis (SSc) and assess its impact on quality of life (QoL). A longitudinal, international observational study followed 189 patients with SSc for a median duration of 5 years (IQR: 4.8–5.3). Presence, subtype and severity of UI, hospital admission and QoL were assessed using serial self-administered questionnaires. Mortality data came from national death registries. Multilevel mixed-effect logistic regressions explored factors associated with UI. Cox models adjusted the effects of UI on hospitalization and death for age, sex and subtype of SSc. Mean annual rates of new-onset UI and remission were 16.3% (95%CI 8.3%–24.2%) and 20.8% (95%CI 12.6–29.1), respectively. Among UI patients, 57.9% (95%CI 51.8–64.0) changed from one UI subtype to another. Between annual questionnaires, the severity of UI was the same in 51.1% (95%CI 40.8–61.4), milder or resolved in 35.2% (95%CI 25.3–44.9), and worse in 13.8% (95%CI 6.7–20.9). Anti-centromere antibodies, digestive symptoms, sex, age, neurological or urological comorbidities, diuretics and puffy fingers were all associated with UI. The two strongest predictors of UI and UI subtypes were a recent UI episode and the subtype of previous leakage episodes. UI at inclusion was not associated with hospital admission (adjusted HR: 1.86; 95%CI 0.88–3.93), time to death (aHR: 0.84; 95%CI 0.41–1.73) or change in QoL over time. Self-reported UI among SSc patients is highly dynamic: it waxes and wanes, changing from one subtype to another over time.
PRISMA_2020_flow_diagram. From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71. For more information, visit:http://www.prisma-statement.org/
Forest plots of the proportion that received corticosteroids (upper panel) and NSAIDs (lower panel)
Forest plots of the proportion that received DMARDS; hydroxychloroquine (upper panel and methotrexate (lower panel)
Forest plots of the proportion that received TNF inhibitors (upper panel) and Azathioprine (lower panel)
We aimed to summarise effects and use of non-pharmacological and pharmacological treatments for sarcoidosis with musculoskeletal manifestations. We systematically searched the Cochrane Library, Ovid MEDLINE, Embase, CINAHL, AMED, Scopus, clinical.trials.gov, PROSPERO and PEDro for systematic reviews from 2014 to 2022 and for primary studies from date of inception to March 29, 2022, and studies with patients diagnosed with sarcoidosis with musculoskeletal manifestations. Inclusion criteria required that studies reported effects of non-pharmacological and/or pharmacological treatments or number of patients receiving these treatments. Results were reported narratively and in forest plots. Eleven studies were included. No systematic reviews fulfilled our inclusion criteria. None of the included studies had a control group. We found that between 23 and 100% received corticosteroids, 0–100% received NSAIDs, 5–100% received hydroxychloroquine, 12–100% received methotrexate, 0–100% received TNF inhibitors, and 3–4% received azathioprine. Only ten patients in one study had used non-pharmacological treatments, including occupational therapy, chiropractic and acupuncture. There are no controlled studies on treatment effects for patients with sarcoidosis with musculoskeletal manifestations. We found 11 studies reporting use of pharmacological treatments and only one study reporting use of non-pharmacological treatments. Our study identified major research gaps for pharmacological and non-pharmacological treatment in musculoskeletal sarcoidosis and warrant randomised clinical trials for both.
The central role of JAK/STAT signalling pathway in IL-17 producing T-cells. IL-6 and IL-23 signals are transduced via JAK2 and TYK2 to STAT3 which triggers production of the effector molecules IL-17 and IL-21. Furthermore, activation of NF-κB by IL-23 results in production of IL-6, further amplifying IL-17 and IL-21 production. Negative feedback is provided by increased expression of SOCS1 and SOCS3 which acto to inhibit JAK2 and STAT3, respectively, limiting further autocrine and paracrine response [31–34]
Ankylosing spondylitis (AS) is a seronegative, chronic inflammatory arthritis with high genetic burden. A strong association with HLA-B27 has long been established, but to date its contribution to disease aetiology remains unresolved. Recent insights through genome wide studies reveal an increasing array of immunogenetic risk variants extraneous to the HLA complex in AS cohorts. These genetic traits build a complex profile of disease causality, highlighting several molecular pathways associated with the condition. This and other evidence strongly implicates T-cell-driven pathology, revolving around the T helper 17 cell subset as an important contributor to disease. This prominence of the T helper 17 cell subset has presented the opportunity for therapeutic intervention through inhibition of interleukins 17 and 23 which drive T helper 17 activity. While targeting of interleukin 17 has proven effective, this success has not been replicated with interleukin 23 inhibition in AS patients. Evidence points to significant genetic diversity between AS patients which may, in part, explain the observed refractoriness among a proportion of patients. In this review we discuss the impact of genetics on our understanding of AS and its relationship with closely linked pathologies. We further explore how genetics can be used in the development of therapeutics and as a tool to assist in the diagnosis and management of patients. This evidence indicates that genetic profiling should play a role in the clinician’s choice of therapy as part of a precision medicine strategy towards disease management.
Patients’ images: a Patient 2: facial swelling, heliotrope erythema. b Patient 1: Gottron papules c Patient 2: magnetic resonance imaging scan (T2) showing bilateral active myositis in the adductors and extensors of the thighs
Methodology flowchart of systematic literature review. n number
Dermatomyositis is a rare, type I interferon-driven autoimmune disease, which can affect muscle, skin and internal organs (especially the pulmonary system). In 2021, we have noted an increase in new-onset dermatomyositis compared to the years before the SARS-CoV-2 pandemic in our center. We present four cases of new-onset NXP2 and/or MDA5 positive dermatomyositis shortly after SARS-CoV-2 infection or vaccination. Three cases occurred within days after vaccination with Comirnaty and one case after SARS-CoV-2 infection. All patients required intensive immunosuppressive treatment. MDA5 antibodies could be detected in three patients and NXP2 antibodies were found in two patients (one patient was positive for both antibodies). In this case-based systematic review, we further analyze and discuss the literature on SARS-CoV-2 and associated dermatomyositis. In the literature, sixteen reports (with a total of seventeen patients) of new-onset dermatomyositis in association with a SARS-CoV-2 infection or vaccination were identified. Ten cases occurred after infection and seven after vaccination. All vaccination-associated cases were seen in mRNA vaccines. The reported antibodies included for instance MDA5, NXP2, Mi-2 and TIF1γ. The reviewed literature and our cases suggest that SARS-CoV-2 infection and vaccination may be considered as a potential trigger of interferon-pathway. Consequently, this might serve as a stimulus for the production of dermatomyositis-specific autoantibodies like MDA5 and NXP2 which are closely related to viral defense or viral RNA interaction supporting the concept of infection and vaccination associated dermatomyositis.
Background Familial Mediterranean fever (FMF) is a disease of the innate immune system. The disease is prevalent in the Mediterranean region. A comprehensive bibliometric analysis of the published literature on FMF indexed in the SCI-Expanded is lacking. Objective To review the global research trend, developments, leading authors, journals, institutions, and countries, and visualization mapping of the published scientific literature on FMF. Methods The data were obtained from SCI-Expanded of the WoSCC database. The obtained data were analyzed using Bibliometrix: An R-tool and an online Bibliometric tool. P-value less than 0.05 was considered statistically significant. Results In this study, a total of 1665 publications (research article, 92% and review, 8%) on FMF were analyzed and characterized. These publications were authored by 5630 authors, and published in 465 journals. The scientific production in FMF research has been increasing over time (p < 0.0001), with scientific annual growth of 3.96%. The most frequent year of publications was 2021 (n = 98), while the most attractive and published journal in FMF research was Rheumatology International (n = 116). The leading institution was Hacettepe University. The top ranked and most cited country in FMF research was Turkey. In total, the authors’ collaboration index was 3.47. Conclusion Generally, FMF scientific research production has increased over the last two decades. The most studied research areas in FMF were rheumatology, general internal medicine and genetics heredity. The most studied recent trend topics in FMF research were validity, reliability, endothelial dysfunction, management, and recommendations. Moreover, regional collaboration between less active countries should be extended in order to expand FMF-related research and thus prevent and control the disease in the near future.
The objective of the study is to report the outcomes of COVID-19 in ANCA-associated vasculitis (AAV) patients. This was a registry-based observational study conducted at a tertiary care center in north India. AAV patients with at least one follow-up visit between March 2020 and September 2021 were included. Demographic features, clinical manifestations, disease activity, and treatment details of underlying AAV were noted in all patients. Details of COVID-19 infection including severity, treatment, and outcomes were noted. Predictors of COVID-19 severity were determined using univariate analysis. A total of 33 (18.3%) out of 180 AAV patients contracted COVID-19 infection. Moderate COVID-19 infection was seen in 33.3% and severe or critical infection was seen in 36.3% of patients. Seventeen patients (51.5%) required supplemental oxygen therapy. Nine patients had active disease at the time of COVID-19 infection and three of them died due to COVID-19 infection. The risk of COVID-19 infection and its severity did not differ between patients receiving different immunosuppressants including rituximab induction. Hypothyroidism (p = 0.046) and ocular (p = 0.038) involvement due to AAV predicted the development of moderate to severe/critical COVID-19. Three (9.1%) patients died from COVID-19 and the rate of AAV flare after COVID-19 was similar to that in non-COVID-19 patients (15.3/100 person-year vs. 15.6/100 person-year, p = 0.95). Majority of the patients with AAV had moderate to severe or critical COVID-19 infection. The rate of death due to COVID-19 in AAV is higher than in general population. Use of standard remission induction regimens did not lead to increased risk of COVID-19 infection in our AAV cohort.
An illustrative example of drugs commonly used in different organ manifestations of patients with SLE. HCQ is recommended in all patients with SLE in the absence of contraindications. Glucocorticoids are commonly used to control disease activity, but daily dose should be reduced to 5–7.5 mg/day prednisone within 3–6 months. Further choice of immunosuppressive agent depends on prevailing manifestation(s), patient preferences access to drugs. NPSLE neuropsychiatric SLE, HCQ hydroxychloroquine, CYC cyclophosphamide, MMF mycophenolate mofetil, AZA azathioprine, CsA cyclosporine A, BEL belimumab, RTX rituximab, TAC tacrolimus, IVIG intravenous immunoglobulin. ¹RTX is off-label and should be used in refractory disease. ²IVIG should be used in case of no response to initial high-dose glucocorticoids or when a rapid increase in platelets or hematocrit is needed. ³EMA and FDA approval pending
Systemic lupus erythematosus (SLE) represents a diagnostic and therapeutic challenge for physicians due to its protean manifestations and unpredictable course. The disease may manifest as multisystemic or organ-dominant and severity at presentation may vary according to age at onset (childhood-, adult- or late-onset SLE). Different manifestations may respond variably to different immunosuppressive medications and, even within the same organ-system, the severity of inflammation may vary from mild to organ-threatening. Current “state-of-the-art” in SLE treatment aims at remission or low disease activity in all organ systems. Apart from hydroxychloroquine and glucocorticoids (which should be used with caution), the choice of the appropriate immunosuppressive agent should be individualized and depend on the prevailing manifestation, severity stratification and patient childbearing potential. In this review, we provide an overview of therapeutic options for the various organ manifestations and severity patterns of the disease, different phenotypes (such as multisystem versus organ-dominant disease), as well as specific considerations, including lupus with antiphospholipid antibodies, childhood and late-onset disease, as well as treatment options during pregnancy and lactation.
Coronal and axial and fat suppression T2-weighted MRI scans of the orbit: Coronal MRI (a) showed high signal intensity in the bilateral extraocular muscles. Axial MRI (b) showed orbital muscles edema with thickening of the belly of the right medial rectus muscle and thickening of the left lateral rectus muscle with high intensity (arrows). Mild regression of orbital muscles edema in coronal (c) and axial (d) MRI
Methodology flowchart
Ocular complications occur in up to one-third of patients with systemic lupus erythematosus (SLE). Among them, orbital myositis (OM) is considered a rare manifestation that affects the extraocular muscles and causes pain and restriction with eye movement. We report a case of OM in a 48-year-old female with SLE and secondary Sjogren’s Syndrome, who presented headache, periorbital edema, and painful ocular movements in both eyes, with no other systemic manifestations. An orbital magnetic resonance image revealed thickening of the right medial rectus and left lateral rectus muscles. Laboratory tests were normal and there was no further disease activity. The patient was treated with prednisone 1 mg/Kg/day with a resolution of symptoms. We found 13 additional cases of OM from our literature review (11 SLE patients and 2 with discoid lupus erythematosus). There was a female predominance in these cases with a mean age of 43.6 years (SD ± 16.9). Their main clinical features included eye pain, swelling, proptosis, diplopia, and limitations in extraocular muscles, while in most of them, there was no other active systemic manifestation. Treatment with steroids led to the complete resolution of symptoms in most of these patients. The available evidence suggests that it is essential to have a high index of suspicion for OM in SLE patients even when there is no systemic disease activity so that proper treatment is initiated early.
Patient recruitment for the study
Psychiatric symptoms in patients with systemic sclerosis (n = 93) as per CIS-R
Receiver operative characteristics (ROC) with the proposed cut off CIS-R score of 10 for a psychiatric diagnosis in systemic sclerosis
There are not many studies looking at psychological impact of physical morbidities amongst patients with systemic sclerosis. Our aim was to describe the prevalence of common mental disorders (CMD) in systemic sclerosis patients, as against the population prevalence of CMDs. We also wanted to assess the utility of revised clinical interview schedule (CIS-R), a standardised interview technique for screening CMDs in systemic sclerosis (SSc). We prospectively recruited 93 consecutive patients fulfilling the 2013 ACR/EULAR criteria for systemic sclerosis from our single tertiary care centre. They were interviewed using CIS-R interviewing technique. These patients were assessed for the presence of psychiatric symptoms and presence of common mental disorders. Various associations of documented mental health issues and ICD-10-based psychiatric diagnosis were also analysed. A total of 29 (31%) out of 93 individuals with systemic sclerosis had a common mental disorder as per the earlier defined CIS-R cut off score of 12 and above. Fatigue (50.5%) and sleep issues (43%) were the commonest symptoms. Thirty-four patients (33.6%) fulfilled a total of 39 ICD-10 psychiatric diagnoses. Total CIS-R score is significantly associated with duration of Scleroderma in univariate analysis (p = 0.019), but there was no significant association on a multivariate analysis. Depression [18.3% as against 5% in Asian Indian general population], followed by obsessive compulsive disorder (OCD) [15.1% as against 0.7% in general population in India] were the top two ICD-10 psychiatric diagnosis in SSc. The occurrence of both depression and OCD, therefore, are far in excess compared to community prevalence. Additionally, modified CIS-R cut off of 10 instead of 12 can also improve the sensitivity (94%) of this screening interviewing tool for an ICD-10 psychiatric diagnosis. Depression is 3.4 times and OCD is 20 times commoner in our cohort of SSc than general population in India. A modified CIS-R cut-off score of 10 may further help in early recognition of these mental disorders in SSc and their referral to a psychiatrist.
Reduction in proteinuria with Tacrolimus in refractory/relapsing LN patients. A Significant decrease in proteinuria (UPCR) at 3 months (p < 0.001) and at 6 months (p < 0.01). Five patients were followed-up further for another 6 months and decrease in proteinuria persisted in them
Improvement in renal SLEDAI with Tacrolimus in refractory/relapsing LN patients. A Significant decrease in rSLEDAI at 3 months (p < 0.01) and at 6 months (p < 0.01)
Change in renal function with Tacrolimus in refractory/relapsing LN patients. A Serum creatinine remained stable in all patients on Tacrolimus over a period of 6 months, except one patient who had increase in serum creatinine at 3 months
Baseline P-gp expression and function on PBL. A P-gp expression on PBL of refractory/relapsing LN patients before Tacrolimus therapy was significantly higher as compared to that in treatment-naive LN patients at baseline (p < 0.01). B P-gp function on PBL of refractory/relapsing LN patients before Tacrolimus therapy was significantly higher as compared to that in treatment-naive LN patients at baseline (p < 0.001)
Change in P-gp expression and function on PBL of refractory/relapsing LN patients with Tacrolimus. A P-gp expression decreased significantly among refractory/relapsing LN patients with Tacrolimus at 3 months (p < 0.05). B P-gp function decreased significantly among refractory/relapsing LN patients with Tacrolimus at 3 months (p < 0.01)
P-glycoprotein (P-gp)-mediated efflux of corticosteroids (CS) may contribute to treatment unresponsiveness in Lupus Nephritis (LN) patients. Tacrolimus is a P-gp inhibitor and hence, may overcome this resistance. We aimed to study the response to tacrolimus, along with the expression and function of P-gp on peripheral blood lymphocytes (PBL) in patients with refractory and relapsing proliferative Lupus Nephritis. We enrolled 12 refractory/relapsing LN patients and treated them with corticosteroids and tacrolimus for 6 months. Expression and function of P-gp on PBL was measured by flow cytometry (as relative fluorescence index, RFI and Rhodamine dye efflux assay) before and 3 months after tacrolimus therapy. Renal response was assessed according to ACR response criteria after 3 and 6 months of tacrolimus therapy. 8 out of 12 refractory/relapsing LN patients achieved renal response (5 partial response, PR and 3 complete responses, CR) as early as 3 months, and 11 patients achieved renal response (7 PR and 4 CR) at 6 months from start of tacrolimus therapy. Proteinuria decreased from median urine protein creatinine ratio (UPCR) of 2.80 (2.00–3.40) at baseline to 1.20 (0.66–1.73) at 3 months (p < 0.001) and to 0.80 (0.19–1.30) at 6 months (p < 0.01). There was significant decrease in P-gp expression [RFI, 3.33 (2.87–4.97) vs 2.03 (1.25–3.86), p < 0.05) and P-gp function (RFI, 55.7 (29.7–84.1) vs 26.8 (16.1–37.0), p < 0.01) after 3 months of tacrolimus therapy. Tacrolimus achieves renal response in refractory/relapsing proliferative LN patients which may be partly related to overcoming P-glycoprotein mediated treatment unresponsiveness.
Lymphocyte characterization by flow cytometry. Gating strategy with representative blots A for B cell subsets and B for T cell subsets and NK cells. Post-sw post-switched memory B cells, plasmabl plasmablasts, DN double negative B cells, gd T γδ T cells
Comparison of lymphocyte subsets of SSc patients without immunosuppressive medication (SScnoIS, white boxes, n = 17) with healthy donors (HD, grey boxes, n = 19). SSc patients had significant lower post-switched memory B cells (A) and within the post-switched memory B cells lower IgA⁺ (B) and IgG⁺ cell numbers (C) compared to HD. Pre-switched memory B cells (D) and transitional B cells (E) were also lower in SScnoIS. Lower T cells (F), lower T helper cell numbers (G), and γδ T cell numbers (H) were present in SScnoIS compared to HD. Boxplots show medians with 25th and 75th percentiles, whiskers indicate minimums and maximums, respectively. *Significant differences in a Mann–Whitney U test, P < 0.05
Comparison of lymphocytes subsets of SSc patients without immunosuppressive medication (SScnoIS, white boxes, n = 17) with SSc patients taking mycophenolate (SSc+MMF, grey boxes, n = 12). SSc+MMF had significant lower T helper cells (A) and lower NK cells (B). Boxplots show medians with 25th and 75th percentiles, whiskers indicate minimums and maximums, respectively. *Significant differences in a Mann–Whitney U test, P < 0.05
Systemic sclerosis (SSc) is a severe chronic disease with a broad spectrum of clinical manifestations. SSc displays disturbed lymphocyte homeostasis. Immunosuppressive medications targeting T or B cells can improve disease manifestations. SSc clinical manifestations and immunosuppressive medication in itself can cause changes in lymphocyte subsets. The aim of this study was to investigate peripheral lymphocyte homeostasis in SSc with regards to the immunosuppression and to major organ involvement. 44 SSc patients and 19 healthy donors (HD) were included. Immunophenotyping of peripheral whole blood by fluorescence-activated cell sorting was performed. Cytokine secretions of stimulated B cell cultures were measured. SSc patients without immunosuppression compared to HD displayed lower γδ T cells, lower T helper cells (CD3 ⁺ /CD4 ⁺ ), lower transitional B cells (CD19 ⁺ /CD38 ⁺⁺ /CD10 ⁺ /IgD ⁺ ), lower pre-switched memory B cells (CD19 ⁺ /CD27 ⁺ /IgD ⁺ ), and lower post-switched memory B cells (CD19 ⁺ /CD27 ⁺ /IgD ⁻ ). There was no difference in the cytokine production of whole B cell cultures between SSc and HD. Within the SSc cohort, mycophenolate intake was associated with lower T helper cells and lower NK cells (CD56 ⁺ /CD3 ⁻ ). The described differences in peripheral lymphocyte subsets between SSc and HD generate further insight in SSc pathogenesis. Lymphocyte changes under effective immunosuppression indicate how lymphocyte homeostasis in SSc might be restored.
Systemic sclerosis illustrated; a UIP pattern was present with myofibroblastic foci (single arrows) and remodeling (A, B, C, D); in (B) the intimate association of lymphocytes with a myofibroblastic focus (single arrow) is a significant feature pointing to an immune disorder with UIP pattern. In (D), the myxoid changes of the intima (double arrow) are seen in a middle-sized pulmonary artery. H&E, bars 100, 50, 20 µm
Hyperplasia of the bronchus-associated lymphoid tissue in two cases of systemic sclerosis with UIP pattern. In (A) myofibroblastic foci in addition to lymph follicles associated with bronchovascular bundles are seen (arrow); in (B) cystic remodeling of lung lobules with mucostasis are seen. H&E, bars 200 µm
Rheumatoid arthritis with lung involvement, one case is illustrated; In A, a dense lymphoid infiltration is seen, myofibroblastic foci (arrows) are in (A) and (B) a loose granuloma (arrow) is shown in (C), and amyloid in (D).H&E, bars 100, 50 µm
SLE illustrated; A shows arterial thrombosis in an organization (arrows), eosinophilic deposits (arrows) mimicking amyloid and unspecific fibrosis is seen in (B), and fibrosis focally OP (arrows) with hemorrhage in C). H&E, bars 200, 100 µm
Sjøgren’s disease illustrated; in (A), organizing pneumonia (arrow) and dense lymphocytic infiltrations are seen, focally (B) showing a lymphoepithelial lesion (double arrow). H&E, bars 100 and 20 µm
Lung involvement in autoimmune diseases (AID) is uncommon, but may precede other organ manifestations. A diagnostic problem is chronicity presenting with lung fibrosis. A new category of interstitial pneumonia with autoimmune features for patients with clinical symptoms of AID and presenting with usual interstitial pneumonia (UIP) enables antifibrotic treatment for these patients. Hypersensitivity pneumonia (HP) and other forms of lung fibrosis were not included into this category. As these diseases based on adverse immune reactions often present with unspecific clinical symptoms, a specified pathological diagnosis will assist the clinical evaluation. We aimed to establish etiology-relevant differences of patterns associated with AID or HP combined with lung fibrosis. We retrospectively evaluated 51 cases of AID, and 29 cases of HP with lung fibrosis, and compared these to 24 cases of idiopathic pulmonary fibrosis (UIP/IPF). Subacute AID and HP most often presented with organizing pneumonia (OP), whereas chronicity was associated with UIP. Unspecified fibrosis was seen in a few cases, whereas NSIP pattern was rare. In 9 cases, the underlying etiology could not be defined. Statistically significant features differentiating chronic AID or HP from UIP/IPF are lymphocytic infiltrations into myofibroblastic/fibroblastic foci. Other features significantly associated with AID and HP were granulomas, isolated Langhans giant cells, and protein deposits, but seen in only a minority of cases. A combination of UIP with one of these features enabled a specific etiology-based diagnosis. Besides the antifibrotic drug regimen, additional therapies might be considered.
The line diagrams show the course of disease in Case 1 (A) and Case 2 (B)
Search strategy for review of literature
Catatonia is a rare psychomotor syndrome characterized by stupor, posturing and echophenomena. It can be associated with schizophrenia, infections, drugs and autoimmune causes like anti N-methyl D-aspartate (NMDA) receptor encephalitis and systemic lupus erythematosus (SLE). Here we report two cases of systemic lupus erythematosus with catatonia, who improved with immunosuppressive treatment and review the cases described in the literature. The first case presented with fever, pancytopenia, toxic epidermal necrolysis (TEN)-like rash and later developed catatonia and macrophage activation syndrome (MAS). The second case presented with acute cutaneous lupus erythematosus (ACLE), fever, alopecia, polyarthralgias, nephritis, cytopenias along with catatonia. Successful management of this syndrome requires prompt recognition and treatment with immunosuppression as well as benzodiazepines with or without electroconvulsive therapy (ECT).
Association between clinical characteristics of RA patients and periodontitis severity. (A) Periodontal status according to the presence of rheumatic nodules. The difference between the two conditions was significative (p = 0.0001) (B) ROC curve for DAS28 and severe PD. Values ≥ 4.1 were indicators of severe PD with 90% specificity and 100% sensitivity (embedded table). Area under the curve =  0.970 ± 0.014 (SD, p < 0.001) (C) Periodontal status according to RA disease activity. DAS28 cutoff value was obtained from the ROC curve shown in B. The difference between the two periodontal profiles was significative (p = 0.0001). (D) ROC curve for RA duration and severe PD. Values ≥ 16 years were indicators of severe PD with 80% specificity and 54% sensitivity (embebed table). Area under the curve =  0.664 ± 0.076 (SD, p = 0.037). (E) Periodontal status according to RA duration. The cutoff value was obtained from the ROC curve shown in D. The difference between the two conditions was significative (p = 0.01). RA rheumatoid arthritis, PD periodontal disease
Rheumatoid arthritis (RA) was significantly associated with increased overall risk of periodontitis, both chronic, inflammatory pathologies leading to connective tissue breakdown and bone destruction. To identify clinical and/or serological variables routinely evaluated during follow-up of people with RA which are associated with the severity of their periodontal disease. An observational, cross-sectional study was carried out, which included RA patients according to ACR/EULAR 2010 criteria having chronic periodontal disease. RA clinical parameters (disease duration, erythrocyte sedimentation rate, serum C-reactive protein, disease activity (DAS28) and rheumatoid factor, presence of bone erosions and rheumatic nodules) and also corticosteroid therapy were considered. Periodontitis was evaluated according to the American Academy of Periodontology (1999) and chronic periodontitis was assessed by full mouth periapical radiographic examination, periodontal probing depth, clinical attachment level and bleeding index. A total of 110 subjects with RA and chronic periodontitis were included. The female/male relation was 5.1, and no significant differences between genres were found in rheumatic or oral variables. RA patients with longer disease duration, higher disease activity and with rheumatic nodules had significantly greater periodontitis severity. Multivariate analysis confirmed that severe periodontitis was associated with DAS28³ 4.1 (OR 51.4, CI 95% 9.4–281.5) and the presence of rheumatic nodules (OR 6.4, CI 95% 1.3–31.6). Disease activity and rheumatic nodules were strongly associated with severe periodontitis. Based on these findings it would be desirable to include interdisciplinary management at an early stage of RA to ensure comprehensive treatment of both pathologies
PA chest radiograph (A) reveals opacification of left lower lung zone (arrows) with indistinct heart border and air-bronchogram. Parenchymal opacification noted in right mid-zone as well (block arrow). CT lung window image (B) shows the collapse of left lower lobe (arrow) with bronchiectasis, lingular collapse (dotted arrow), and right middle lobe collapse (block arrow). The presence of multiple lobar collapse with bronchiectasis with a lower lobar preponderance suggested the possibility of underlying immunodeficiency
Monogenic lupus is a subset of lupus caused by single-gene disorders, integrating the paradoxical combination of autoimmunity and immunodeficiency. Pulmonary manifestations with recurrent pneumonia and bronchiectasis have rarely been described as the predominant presentation of juvenile lupus and may suggest an alternate differential like primary immunodeficiency, especially in early childhood. We describe a case of 10-year girl who presented with a history of recurrent pneumonia, arthritis, alopecia, and poor weight gain for the past 2 years. On examination, she had respiratory distress, bilateral diffuse crackles and arthritis of the small joints of hands. Lab investigations showed pancytopenia, low complement levels and high titers of ANA and anti-dsDNA antibodies. The patient was diagnosed with juvenile lupus. Imaging studies revealed evidence of multiple lobar collapse and consolidation with bronchiectasis. She was started on steroids, HCQ and supportive measures for bronchiectasis. The child reported relief in initial symptoms of lupus on follow-up but developed recurrent thrombocytopenia requiring IVIG and escalating the doses of oral steroids. The young age and atypical presentation prompted a screening for monogenic lupus, and clinical exome sequencing revealed a novel homozygous missense variation in exon 20 of the C4Agene with clinically reduced C4 levels, consistent with the diagnosis of C4A deficiency.
Histopathological analysis on hematoxylin and eosin (H&E) staining showing focal lymphocytic sialadenitis in minor salivary gland biopsy specimens obtained from primary Sjögren's syndrome patients. In these cases, several foci were observed (white arrowheads), containing germinal center-like structures (black arrowheads) (A and B, × 2.5; C, × 5; D and E, × 10; and F, × 40). Similarly, notice focal lymphocytic sialadenitis in oral reactive lesions obtained from non-Sjögren's syndrome non-sicca patients. In these cases, several foci (white arrowheads) were observed, containing germinal center-like structures (black arrowheads) (G, H and I, × 4; J, K and L, × 40). The squares in G, H and I are shown in increasing magnification in J, K and L, respectively
Immunohistochemical analysis in consecutive (serial) sections of focal lymphocytic sialadenitis in minor salivary gland biopsy specimen obtained from primary Sjögren’s syndrome patient A–F. In this case, notice germinal center-like structures showing strong positivity for Bcl-6 (A and D), CD23 (B and E) and CD10 (C and F) (A, B and C, × 10; D, E and F, × 40). The D, E and F photomicrographs represent higher magnification of A, B and C photomicrographs, respectively. Similarly, notice the immunohistochemical analysis in consecutive (serial) sections of focal lymphocytic sialadenitis in oral reactive lesion obtained from non-Sjögren's syndrome non-sicca patient, which showed germinal center-like structures with positivity for Bcl-6 (G and J), CD23 (H and K) and CD10 (I and L) (G, H and I, × 10; J, K and L, × 40). The J, K and L photomicrographs represent higher magnification of G, H and I photomicrographs, respectively
Focal lymphocytic sialadenitis (FLS), an important diagnostic criterion for Sjögren’s syndrome (SS) diagnosis, can also be observed when assessing minor salivary gland (mSG) biopsies from healthy asymptomatic individuals (non-SS patients). Fifty cases of primary SS (pSS group) and 31 cases of oral reactive lesions (non-SS non-sicca group) containing also typical FLS features, were assessed by morphological and immunohistochemical (CD10, CD23 and Bcl-6) analysis, aiming at the detection of GCs. All pSS cases showed FLS with focus score (FS) ≥ 1. In the non-SS non-sicca group, 12, 10 and 9 cases showed FLS with FS ≥ 1, FLS with FS < 1 and FLS associated with chronic sclerosing sialadenitis with FS < 1, respectively. The morphological analysis revealed similar frequency of GCs in pSS (20%) and non-SS non-sicca group (19%). The area (p = 0.052) and largest diameter (p = 0.245) of GCs were higher in pSS than non-SS non-sicca group. The FS and number of foci were significantly higher in pSS than non-SS non-sicca group with FS < 1. Immunohistochemistry confirmed all morphological findings (GCs showing CD23 and Bcl-6 positivity, with variable CD10 expression) and additionally in 3 and 1 cases of the pSS and non-SS non-sicca group, respectively. Moreover, another 6 and 2 cases of the pSS and non-SS non-sicca group with FS ≥ 1, respectively, showed positivity only for CD23. FLS can also be observed when assessing oral reactive lesions, which showed similar frequency of GCs with those found in pSS patients. Further studies, including functional analysis of lymphocytic populations and GCs in FLS, are encouraged.
Association of drugs with TST response and QTF-GT results
It is assumed that in candidates for TNF-alpha inhibitor (TNFi) treatment, tuberculin skin test (TST) may be unreliable, since BCG vaccination causes false positive and drugs cause false negative results, favoring the use of Quantiferon or T-spot assays. However, these tests may not be readily available in all parts of the world. We aimed to determine the reliability of TST with respect to BCG vaccination and drugs in candidates for TNFi treatment, and how isoniazid is tolerated, assuming that the use of TST would result in increased isoniazid use. We included 1031 adult patients who were prescribed a TNFi for the first time. We analysed the association of BCG and drugs with TST and Quantiferon results, the determinants of a positive TST, and evaluated the tolerability of isoniazid. BCG vaccination and male sex were associated with positive TST (OR 3.56, 95% CI 1.98–6.41 and OR 2.54, 95% CI 1.75–3.68, respectively), while prednisolone and azathioprine were associated with negative TST (OR 0.63, 95% CI 0.43–0.91 and OR 0.40, 95% CI 0.11–0.76). Isoniazid was prescribed to 684 (66.3%) patients and had to be discontinued in 12.2% of these before 9 months, most commonly due to hepatotoxicity (44%). One patient developed tuberculosis despite isoniazid use. BCG vaccination may be associated with false positive TST, despite a long time since vaccination in candidates for TNFi treatment. Prednisolone and azathioprine use were associated with negative TST. Despite the high frequency of isoniazid use associated with using TST instead of QTF, isoniazid was generally well tolerated.
Flowcharts of the literature search
Clinical pictures of the present case. a Puffy fingers. b Skin sclerosis and pigmentation of anterior chest
Magnetic resonance imaging findings of bilateral posterior cervical muscles. Coronal (a) and horizontal (b) images before treatment show the gadolinium enhancement of bilateral posterior muscles (yellow arrow). Coronal (c) and horizontal (d) images after immunosuppressive treatment demonstrate the improved enhancement of gadolinium on bilateral posterior muscles (yellow arrow)
Magnetic resonance imaging findings of proximal lower extremities. a Image before treatment shows the gadolinium enhancement of proximal lower extremities (yellow circle). b Image after immunosuppressive treatment demonstrates the improved enhancement of gadolinium on proximal lower extremities (yellow circle)
Dropped head syndrome is a rare disease entity characterized by severe weakness of the cervical para-spinal muscles, resulting in a chin-on-chest deformity. Systemic sclerosis is one of the causes of dropped head syndrome, but its characteristics and prognosis remain unclear due to the extreme rarity of this condition. We present a case of dropped head which occurred in systemic sclerosis. He presented with severe dropped head and relatively mild weakness of the proximal limb muscles. Serum level of creatine kinase was elevated, myopathic change was observed in electromyography, and gadolinium enhancement was found in magnetic resonance imaging of his posterior neck muscles. Anti-topoisomerase I antibody was positive, while other autoantibodies such as anti-PM/Scl and anti-Ku antibodies were negative. Since his dropped head acutely progressed, high dose of glucocorticoid therapy was initiated, which successfully improved dropped head, serum level of creatine kinase, and gadolinium enhancement in magnetic resonance imaging. Our present case and literature review suggest that dropped head occurring in systemic sclerosis can be treatable with immunosuppressive therapy. It is important to recognize this rare but treatable involvement of systemic sclerosis because early diagnosis and treatment initiation are crucial to prevent the irreversible organ damage and the significant decrease of daily activities.
Nailfold Video Capillaroscopy (NFVC) in MCTD, RNP-positive SLE and RNP-negative SLE. a and b: NFVC in a patient with MCTD showing decreased capillary density, giant capillary, ramified capillaries and avascular areas. c and d: NFVC images in a patient with RNP-positive SLE showing reduced capillary density, avascular areas and ramified capillaries; but these are seen in lesser intensity as compared to 1a and 1b (MCTD). e and f: NFVC images in RNP-negative SLE case show higher capillary density with no avascular area as compared with RNP-positive SLE and MCTD
Anti-U1RNP antibody is associated with distinct organ involvement in patients with systemic lupus erythematosus (SLE). Nailfold capillaroscopy (NFC) allows non-invasive assessment of microvascular abnormalities in several connective tissue diseases. The objective of this study is to determine the association of anti-U1RNP antibody with microvascular changes by NFC in RNP-positive SLE patients in comparison with RNP-negative SLE patients (negative disease controls) and mixed connective tissue disease (MCTD) cases (positive disease controls). NFC examination was performed in consecutive patients with SLE with or without anti-U1RNP positivity. MCTD patients were recruited as disease controls. Abnormalities noted in the three groups were compared using non-parametric tests. Ordinal logistic or linear regression was used wherever applicable. 81 patients were studied, of whom 28 were diagnosed as RNP-positive SLE (age 30.0 ± 10.37; 26 females), 26 were RNP-negative SLE (age 29.42 ± 9.20; 25 females) and 27 had MCTD (age36.5 ± 9.70; 25 females). RNP-positive SLE patients had more frequent giant capillaries, enlarged capillaries and ramified capillaries as compared to RNP-negative SLE (p = 0.05, < 0.01 and 0.03, respectively). The capillary density was lower in patients with MCTD as compared with patients with RNP-positive SLE (5.11 ± 1.69/mm vs 7.25 ± 1.38/ mm, p < 0.01) and RNP-negative SLE (8.92 ± 1.13/mm, p < 0.01). The reduction in capillary density was less severe in patients with RNP-negative SLE as compared with RNP-positive SLE (OR = 0.1058 [95% CI = 0.02–0.546], p < 0.01) which was independent of the presence of Raynaud’s phenomenon, interstitial lung disease and disease duration. Presence of anti-U1RNP antibody is associated with notable patterns of microvascular abnormalities in SLE. These NFC abnormalities are noted more profoundly in patients with MCTD and are less marked in RNP-negative SLE patients.
Clinical and radiologic characteristics of IPAF patients: photosensitive skin rash involving the face sparing the nasolabial fold (a), and over back (b); inflammatory arthritis involving the proximal interphalangeal joints of hand (c); Raynaud’s phenomenon (d); ground glass opacities (blue arrowhead) and fibrotic bands with traction bronchiectasis (white arrowhead) as seen on axial section of high-resolution computerized tomography (HRCT) of thorax suggestive of fibrotic non-specific interstitial pneumonia, and (e) and honeycombing and cystic changes (blue arrow) as seen on axial sections of HRCT suggestive of usual interstitial pneumonia (f)
The current study aimed to characterize patients from a rheumatology referral center in north India, who satisfied the definition of interstitial pneumonia with autoimmune features (IPAF) as given by the American Thoracic Society and European Respiratory Society (ATS/ERS) consensus committee in 2015. Thirty-five adult patients aged 18 years and above, fulfilling the 2015 ATS/ERS criteria for IPAF were included in the study. The clinical and immunological profile, and radiologic findings on high-resolution computerized tomography thorax were noted. Antinuclear antibody (ANA) by indirect immunofluorescence at 1:320 titer and myositis-specific antibody (MSA) assays were performed. Non-parametric tests were used to compare variables between groups. The study cohort included predominantly female patients with a mean age of 50.6 ± 13 years and mean duration of disease of 38.8 ± 28.4 months. Majority of patients (49%) fulfilled the morphologic and serologic domains as per the IPAF consensus criteria and 31% patients had features in all three domains. Non-specific interstitial pneumonia was the most common pattern observed in 77% patients. Raynaud’s phenomenon and inflammatory arthritis were the predominant autoimmune features. Pulmonary arterial hypertension was documented in 60% of patients on echocardiography. Positive ANA at 1:320 dilution was present in all 26 patients tested, whereas extractable nuclear antigen and MSA assays detected autoantibodies in 49% and 51% of patients respectively. IPAF predominantly affected females in the age group of 50 years and above, with varied autoimmune manifestations and autoantibody profile.
Contrast enhanced computed tomography showing bulky pancreas in a lupus patient with acute pancreatitis
Proposed algorithm for diagnosis and management of AP in SLE
Acute pancreatitis (AP) is a rare but life threatening manifestation of Systemic Lupus Erythematosus (SLE). The current study aims to study the clinical characteristics, severity, mortality, and outcome of SLE-related AP in Indian population. We retrospectively reviewed medical records of patients with SLE who had AP in the past. Data from 13 rheumatology centers across India were compiled. All patients satisfied SLICC criteria for SLE and ATLANTA criteria for AP. AP was classified in to mild, moderate and severe using revised Atlanta classification. Patients with known risk factors like gall stone and alcohol were excluded.Sixty-six patients (six, children) were studied. Majority of patients were females (82%). The median age of presentation was 24 (11–63) years and most patients (57.5%) presented within first year of diagnosis of lupus. AP occurred mostly in the setting of active lupus (89%). Active nephritis was seen in 39% while a fourth had CNS disease. Patients with severe AP had lower C3. Ascites and sepsis were most common local and systemic complications, respectively. Mortality was 17%. Hypocalcemia, presence of sepsis and shock predicted mortality. In the multivariate analysis, only presence of shock remained as independent predictor of death (OR 63.0, 95% CI: 5.2–760.3). Pancreatitis is an early manifestation of SLE and is associated with active disease. Significant mortality is seen particularly with severe pancreatitis.
Comparison of the mean difference of FSFI global and its domains between pSS patients and healthy controls. Bars indicates SD
Mucosal dryness and dyspareunia are symptoms that may signifcantly afect women with primary Sjӧgren syndrome (pSS). We investigated whether vaginal dryness is correlated with sexual function, and the impact may have on the quality of life (QoL) and mental health well-being in pSS patients. Ethically approved comparative cross-sectional study was designed to assess sexual function using the Female Sexual Function Index (FSFI) in 65 pSS female patients vs 62 sex-matched controls. The efect of vaginal dryness and fatigue on sexual function was investigated. Vaginal dryness was correlated with oral dryness estimated by salivary fow rate and the Clinical Oral Dryness Score to investigate whether genital dryness is indicative of general mucosal dryness in pSS. Validated questionnaires were used to investigate the efect of sexual function on QoL and mental health well-being. The number of sexually active pSS participants was signifcantly less than in the control group (28/65 vs 42/62, p<0.05). The sexual function was signifcantly impaired in the pSS group (mean FSFI=19 vs 28.3, p<0.05). There was no signifcant association between self-reported vaginal dryness and oral dryness or sexual function. The open-ended questions showed that the most troublesome symptom reported by pSS patients was oral dryness (43%, n=28/65) followed by fatigue (31%, n=20/65). Sexual dysfunction had a negative impact on QoL and the mental health well-being of pSS patients in all aspects, especially on the quality of social life (β=0.7, p=0.02). Addressing sexual dysfunction can potentially improve the QoL of pSS patients signifcantly, especially their social well-being.
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and has been implicated in pathogenesis of ankylosing spondylitis (AS). CD 74 is the receptor for MIF and IgA antiCD74 autoantibodies have been described from different parts of the world in patients with AS. As enthesitis-related arthritis (ERA) is a form of juvenile spondyloarthropathy, we studied the serum and synovial fluid levels of MIF in ERA and looked for the IgA antiCD74 antibodies in patients with ERA in our population. Patients with JIA (ILAR classification) were studied. Serum MIF levels were measured by ELISA in 101 patients of ERA (synovial fluid also where available) and compared to 28 patients of other categories of JIA, 25 patients each of ankylosing spondylitis and rheumatoid arthritis, and 38 healthy controls. In addition, association of MIF with disease activity was assessed. Ig A antiCD74 antibodies were measured in sera of ERA, AS and healthy controls. Median serum MIF levels were higher in ERA [2.50 (1.20-4.85) ng/ml] than in healthy controls [0.28 (0.16-0.48); p < 0.0001] and patients with RA [1.13 (0.44-2.45); p < 0.01] MIF levels in ERA were comparable to other categories of JIA [2.63 (1.70-4.05)] and patients with AS [3.62 (0.52-6.51)]. Synovial fluid MIF levels were higher than serum levels (p < 0.01). Serum MIF level had an association with the JSpADA score (r = 0.29, p < 0.01). Serum MIF levels had no association with presence of inflammatory markers, enthesitis, inflammatory back pain or sacroiliitis. IgA AntiCD74 antibody was positive only in 3/88 (3.41%) of ERA patients and was not detected in any patients of AS or healthy controls. Patients with ERA have high MIF levels that show modest correlation with disease activity. Higher synovial fluid MIF levels suggest that it may play a role in synovitis seen in ERA. IgA antiCD74 antibodies are rarely seen in ERA.
Anti-U1-RNP antibodies are necessary for the diagnosis of mixed connective tissue disease (MCTD), but they are also prevalent in other connective tissue diseases, especially systemic lupus erythematosus (SLE), from which distinction remains challenging. We aimed to describe the presentation and outcome of patients with anti-U1-RNP antibodies and to identify factors to distinguish MCTD from SLE. We retrospectively applied the criteria sets for MCTD, SLE, systemic sclerosis (SSc) and rheumatoid arthritis (RA) to all patients displaying anti-U1-RNP antibodies in the hospital of Caen from 2000 to 2020. Thirty-six patients were included in the analysis. Eighteen patients (50%) satisfied at least one of the MCTD classifications, 11 of whom (61%) also met 2019 ACR/EULAR criteria for SLE. Twelve other patients only met SLE without MCTD criteria, and a total of 23 patients (64%) met SLE criteria. The most frequent manifestations included Raynaud’s phenomenon (RP, 91%) and arthralgia (67%). We compared the characteristics of patients meeting only the MCTD (n = 7), SLE (n = 12), or both (n = 11) criteria. Patients meeting the MCTD criteria were more likely to display SSc features, including sclerodactyly (p < 0.01), swollen hands (p < 0.01), RP (p = 0.04) and esophageal reflux (p < 0.01). The presence of scleroderma features (swollen hands, sclerodactyly, gastro-oesophageal reflux), was significantly associated with the diagnosis of MCTD. Conversely, the absence of those manifestations suggested the diagnosis of another definite connective tissue disease, especially SLE.
Despite many approaches, diagnosis of fibromyalgia (FM) remains a difficult clinical task, especially in the case of comorbidity of FM with other rheumatic diseases, such as ankylosing spondylitis (AS). The prevalence of FM among the population is 2.9–4.7%; whereas in patients with AS, it increases to 12.6–28.5%. The aim of the study was to evaluate the prevalence of FM in AS patients according to different criteria and to characterize them. 143 patients with AS, according to the modified New York Criteria, were examined. The FiRST used for screening of a possible FM. The FM was detected using the ACR 1990 criteria, mARC 2010, ACR 2016 and AAPT 2019 diagnostic criteria. All data were analyzed using IBM Statistics SPSS 22 software. The study was carried out in compliance with bioethical standards. According to ACR 1990, mACR 2010, ACR 2016, and AAPT 2019, the prevalence of FM in patients with AS ranged from 21.0% to 35.7%. The strongest correlation was observed in the mACR 2010 and ACR 2016 criteria (Cohen’s κ = 0.871, p < 0.001); ACR 1990 and mACR 2010 as well as ACR 2016 criteria also demonstrated quite a strong level of agreement (Cohen’s κ = 0.675 and 0.684, p < 0.001). Our results showed a high prevalence of FM in AS patients. mACR 2010 and ACR 2016 criteria are optimal for clinical practice to diagnose FM in AS patients.
Brain MRI upon arrival. Axial T2 weighted/FLAIR images of brain MRI: a,b,c demonstrate diffuse hyperintensity within the right and left periventricular white matter, right corona radiata, right and left centrum semiovale and right basal ganglia. d axial DWI demonstrates restricted diffusion in the head of the right caudate nucleus. e post gadolinium T1W1 showed less pathological enhancement in the corresponding regions of the right caudate nucleus and right corona radiate. f T2* weighted sequence detected hemosiderin deposition in right corona radiata
Brain MRI 4 months after methotrexate discontinuation. Axial T2 weighted/FLAIR images of brain MRI: a,b,c demonstrate less significant hyperintensity within the right and left periventricular white matter, right corona radiata, right and left centrum semiovale and right basal ganglia. d axial DWI reveals resolution of restricted diffusion in the head of the right caudate nucleus. e post gadolinium T1W1 showed pathological enhancement only in the right caudate nucleus. f T2* weighted sequence detected hemosiderin deposition in right corona radiata
Rheumatoid arthritis (RA) is a systemic inflammatory disease treated with conventional and biologic disease-modifying drugs. Methotrexate is the anchor drug for the treatment of RA and is also frequently used for various autoimmune diseases. Adverse events are common and generally easy to manage, involving mainly the gastrointestinal tract and the liver function. However, neurotoxicity is very uncommon in adults with rheumatic diseases. B cell depletion with rituximab is another therapy approach particularly in patients with refractory RA. Whistle leukoencephalopathy - namely progressive multifocal leukoencephalopathy-is an infrequent but well-described side effect of rituximab. In contrast, central nervous system toxicity due to methotrexate is extremely rare especially in RA individuals under oral or subcutaneous low dose on weekly basis. We present a challenging case of a RA patient on treatment with methotrexate and rituximab presenting with leukoencephalopathy. The patient was diagnosed with methotrexate-induced leukoencephalopathy which reversed after treatment discontinuation. We comment on the symptoms and diagnostic workout and we review the available literature on this issue based on recommendations for narrative reviews.
Although the importance of the biopsychosocial model that aims the optimum treatment is emphasized in the literature, there is a lack of scales that evaluate individuals with PsA in a multi-dimensional way, including all areas of influence. This study aimed to determine the validity, reliability, and responsiveness of the Cognitive Exercise Therapy Approach-Biopsychosocial Questionnaire (BETY-BQ) in individuals diagnosed with Psoriatic Arthritis (PsA). Psoriatic Arthritis Quality of Life Questionnaire (PsAQoL), Health Assessment Questionnaire, Hospital Anxiety and Depression Scale, and Short Form-36 were used for the validity of the BETY-BQ. For scale reliability, the test-retest method was performed, Intraclass Correlation Coefficient (ICC) was calculated, and Cronbach's alpha (α) coefficient was checked for internal consistency. For the responsiveness of the scale, all scales were re-applied with 3 months intervals. The correlations of BETY-BQ with the other scales were found medium to very high. ICC was analyzed to compare the reliability of the test-retest results and it was found to be excellent. Cronbach's α value was found to be 0.940 which showed an excellent internal consistency. The time-dependent change sensitivity of BETY-BQ was found to be highly correlated with the PsA-specific scale, the PsAQoL questionnaire. BETY-BQ was determined as a valid, reliable, and sensitive assessment tool that health professionals can use in individuals with PsA diagnosis. In this study, a scale that will reveal the biopsychosocial responses of individuals with PsA to pharmacological and non-pharmacological treatments was presented to the literature.
Top-cited authors
Young Ho Lee
  • Chungnam National University
George Kitas
  • The Dudley Group NHS Foundation Trust
Najia Hajjaj-Hassouni
  • Mohammed V University of Rabat
Surjit Singh
Ozgur Kasapcopur
  • Istanbul University-Cerrahpasa