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Alopecia totalis (AT) is characterised by extensive hair loss on the scalp, and common treatments are rarely effective. Janus kinase inhibitors represent a potentially new treatment modality in AT. In this case report, AT was successfully treated with tofacitinib in a 43-year-old male patient. After six months of treatment, the patient regained all his hair, and no relapse was seen after one year of treatment.

Objectives: To examine whether MRI assessed inflammation and damage in the wrist of patients with early rheumatoid arthritis (RA) are associated with patient-reported outcomes (PROs)., Methods: Wrist and hand MRIs of 210 patients with early RA from two investigator-initiated, randomised controlled studies (CIMESTRA/OPERA) were assessed according to the Outcome Measures in Rheumatology RA MRI score (RAMRIS) for synovitis, tenosynovitis, osteitis, bone erosions and joint space narrowing (JSN) at baseline, 1 and 5 years follow-up. These features, and changes therein, were assessed for associations with health assessment questionnaires (HAQ), patient global visual analogue scales (VAS-PtGlobal) and VAS-pain using Spearman's correlations, generalised estimating equations and univariate/multivariable linear regression analyses. MRI features were further tested for trends against specific hand-related HAQ items using Jonckheere trend tests., Results: MRI inflammation, but not damage, showed statistically significant associations with HAQ, VAS-PtGlobal and VAS-pain for status and change scores, independently of C reactive protein and swollen joint count. MRI-assessed synovitis was most consistently associated with PROs, particularly VAS-PtGlobal and VAS-pain. MRI-assessed synovitis and tenosynovitis mean scores were positively associated with patient-reported difficulty to cut meat and open a milk carton (p<0.01), and similar patterns were seen for other hand-related HAQ items. Incorporating metacarpophalangeal joints in the analyses did not strengthen the associations between MRI pathology and PROs., Conclusions: MRI-assessed inflammation, but not damage, in early RA wrists is associated with patient-reported physical impairment, global assessment of disease activity and pain and influences the physical function in the hand., Trial Registration Number: NCT00660647., Competing Interests: Competing interests: MLH: research support and grants from: BMS, AbbVie, Pfizer, UCB-Nordic, MSD and Biogen; consultation fees from: Orion, KH-P: consultation fees from: AbbVie and UCB, MBA: research support and grants from: AbbVie, MØ: consultation fees from: AbbVie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB, Wyeth; research support and grants from: AbbVie, BMS, Janssen and Merck., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To investigate the short-term and long-term efficacy of intra-articular betamethasone injections, and the impact of joint area, repeated injections, MRI pathology, anticyclic citrullinated peptide (CCP) and immunoglobulin M rheumatoid factor (IgM-RF) status in patients with early rheumatoid arthritis (RA)., Methods: During 2 years of follow-up in the CIMESTRA trial, 160 patients received intra-articular betamethasone in up to four swollen joints/visit in combination with disease-modifying antirheumatic drugs. Short-term efficacy was assessed by EULAR good response. Long-term efficacy by Kaplan-Meier plots of the joint injection survival (ie, the time between injection and renewed flare). Potential predictors of joint injection survival were tested., Results: 1373 Unique joints (ankles, elbows, knees, metacarpophalangeal (MCP), metatarsophalangeal, proximal interphalangeal (PIP), shoulders, wrists) were injected during 2 years. 531 Joints received a second injection, and 262 a third. At baseline, the median numbers of injections (dose of betamethasone) was 4 (28 mg), declining to 0 (0 mg) at subsequent visits. At weeks 2, 4 and 6, 50.0%, 58.1% and 61.7% had achieved a EULAR good response. After 1 and 2 years, respectively, 62.3% (95% CI 58.1% to 66.9%) and 55.5% (51.1% to 60.3%) of the joints injected at baseline had not relapsed. All joint areas had good 2-year joint injection survival, longest for the PIP joints: 73.7% (79.4% to 95.3%). 2-Year joint injection survival was higher for first injections: 56.6% (53.7% to 59.8%) than for the second: 43.4% (38.4% to 49.0%) and the third: 31.3% (25.0% to 39.3%). Adverse events were mild and transient. A high MRI synovitis score of MCP joints and anti-CCP-negativity were associated with poorer joint injection survival, whereas IgM-RF and C-reactive protein were not., Conclusion: In early RA, intra-articular injections of betamethasone in small and large peripheral joints resulted in rapid, effective and longlasting inflammatory control. The cumulative dose of betamethasone was low, and the injections were well tolerated.

Objective: Cyclic citrullinated peptide antibody (anti-CCP)-positive and anti-CCP-negative rheumatoid arthritis (RA) have been suggested as 2 distinctive disease subsets with respect to disease activity and prognosis. Previously, we proposed that anti-CCP antibodies might have a chondrocyte-suppressive effect. We aimed to compare circulating cartilage oligomeric matrix protein (COMP), a marker of cartilage turnover, in untreated anti-CCP-positive and anti-CCP-negative RA, and to study the temporal pattern of COMP through 4 years of treatment, including the relationship to imaging and clinical findings., Methods: A total of 160 patients with newly diagnosed RA who were naive to disease-modifying antirheumatic drugs were included in the CIMESTRA trial. Ninety healthy blood donors served as controls. Demographic and disease measures including Disease Activity Score in 28 joints, IgM rheumatoid factor, anti-CCP, Health Assessment Questionnaire, visual analog scale scores for pain and global and physician assessment, and magnetic resonance imaging (MRI) of the nondominant hand were recorded at baseline. COMP in serum was measured by ELISA at inclusion and serially through 4 years., Results: Median baseline COMP was higher in patients with RA [9.8 U/l (interquartile range 8.96, 10.5)] compared with controls [8.3 U/l (IQR 7.84, 8.9); p < 0.001] and remained elevated at 4 years [10.8 U/l (IQR 10.2, 11.7); p < 0.001]. At baseline, anti-CCP-positive patients had lower COMP than anti-CCP-negative patients (p = 0.048). In anti-CCP-positive patients, COMP exhibited a parabolic course over 4 years, while COMP in anti-CCP-negative patients had an almost linear course. In anti-CCP-positive patients, COMP was associated with MRI edema and erosion score, while COMP was correlated with synovitis score in anti-CCP-negative individuals., Conclusion: Our study provides additional evidence for the existence of different disease pathways in anti-CCP-positive and anti-CCP-negative subsets of RA, and evidence that anti-CCP antibodies may be implicated in the disease process by modifying cartilage metabolism.

Objective: To investigate the relationship between markers of collagen II synthesis and degradation with disease activity measures, autoantibodies, and radiographic outcomes in a 4-year protocol on patients with early rheumatoid arthritis (RA) who are naïve to disease-modifying antirheumatic drugs., Methods: One hundred sixty patients with newly diagnosed, untreated RA entered the Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA) trial. Disease activity and radiograph status were measured at baseline and 4 years. The N-terminal propeptide of collagen IIA (PIIANP) and the cross-linked C-telopeptide of collagen II (CTX-II) were quantified at baseline by ELISA. PIIANP was also assayed at 2 and 4 years. Anticyclic citrullinated peptide (anti-CCP) was recorded at baseline. An uncoupling index for cartilage collagen metabolism was calculated from PIIANP and CTX-II measurements., Results: PIIANP was low at diagnosis and 4 years on (p < 0.001), irrespective of treatment and disease activity. PIIANP was lowest in anti-CCP positive patients (p = 0.006), and there was a negative correlation between PIIANP and anti-CCP titers (rho = -0.25, p 0.002). CTX-II was increased (p < 0.001) and correlated positively with disease activity and radiographic progression, but not with anti-CCP (p = 0.93). The uncoupling index was not superior to CTX-II in predicting radiographic changes., Conclusion: These results suggest that cartilage collagen formation and degradation are unbalanced when RA is diagnosed. The different associations of collagen II anabolism (PIIANP) and collagen II degradation (CTX-II) with anti-CCP, synovitis, and radiographic progression indicate that at this early stage of RA, cartilage collagen degradation is mainly driven by synovitis, while anti-CCP antibodies may interfere with cartilage regeneration by inhibiting collagen IIA formation. Trial registration j.nr NCT00209859.

Surfactant protein D (SP-D) is an oligomeric calcium-dependent lectin with important roles in innate host defence against infectious microorganisms. Several studies have shown that patients with inflammatory lung disease have elevated levels of circulating SP-D, and serum SP-D has been suggested to be used as a biomarker for disease e.g. in COPD. We aimed to investigate the variation of circulating SP-D in healthy individuals in and between days for 6 months. In addition, we studied the SP-D response to a standardized physical exercise programme. SP-D was measured in serum using a 5-layered ELISA technique. We found that circulating SP-D remained constant over a 6-month period. However, during the course of one day SP-D varied significantly. Median SP-D peaked at 10 a.m. at 1009 ng/ml (95% CI: 803-1497), subsequently decreasing to nadir at 10 p.m. at 867 ng/ml (95% CI: 650-1148)(P<0.00005). Median pre-exercise level of SP-D was 746 ng/ml (95% CI: 384-2035), and immediately after cessation of physical activity the median SP-D level was 767 ng/ml (95% CI: 367-1885) (P=0.248). Our findings underscore the importance of standardized blood sampling conditions in future studies on the potential role of SP-D as a biomarker. Importantly, stable measures of systemic SP-D over a prolonged period support that SP-D is suitable for biomarker studies., (2009 Elsevier GmbH. All rights reserved.)

Introduction: Surfactant protein D (SP-D) is a collectin with immuno-regulatory functions, which may depend on oligomerization. Anti-microbial and anti-inflammatory properties have been attributed to multimeric SP-D variants, while trimeric subunits per se have been suggested to enhance inflammation. Previously, we reported low circulating SP-D in early rheumatoid arthritis (RA), and the present investigation aims to extend these data by serial SP-D serum measurements, studies on synovial fluid, SP-D size distribution and genotyping in patients with early RA., Methods: One-hundred-and-sixty disease-modifying antirheumatic drug (DMARD) naïve RA patients with disease duration less than six months were studied prospectively for four years (CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) trial) including disease activity measures (C-reactive protein, joint counts and Health Assessment Questionnaire (HAQ) score), autoantibodies, x-ray findings and SP-D. SP-D was quantified by enzyme-linked immunosorbent assay (ELISA) and molecular size distribution was assessed by gel filtration chromatography. Further, SP-D Met11Thr single nucleotide polymorphism (SNP) analysis was performed., Results: Serum SP-D was significantly lower in RA patients at baseline compared with healthy controls (P < 0.001). SP-D increased slightly during follow-up (P < 0.001), but was still subnormal at four years after adjustment for confounders (P < 0.001). SP-D in synovial fluid was up to 2.5-fold lower than in serum. While multimeric variants were detected in serum, SP-D in synovial fluid comprised trimeric subunits only. There were no significant associations between genotype distribution and SP-D. Baseline SP-D was inversely associated to CRP and HAQ score. A similar relationship was observed regarding temporal changes in SP-D and CRP (zero to four years). SP-D was not associated to x-ray findings., Conclusions: This study confirms that circulating SP-D is persistently subnormal in early and untreated RA despite a favourable therapeutic response obtained during four years of follow-up. SP-D correlated negatively to disease activity measures, but was not correlated with x-ray progression or SP-D genotype. These observations suggest that SP-D is implicated in RA pathogenesis at the protein level. The exclusive presence of trimeric SP-D in affected joints may contribute to the maintenance of joint inflammation., Trial Registration: (j.nr NCT00209859).

Objective: To study the association between polymorphisms in the mannose-binding lectin gene (MBL2) and disease activity, physical disability, and joint erosions in patients with newly diagnosed rheumatoid arthritis (RA)., Methods: Patients with early RA (n=158) not previously treated with disease modifying antirheumatic drugs, participating in a treatment trial (CIMESTRA study) were examined at inclusion for MBL2 pooled structural genotypes (O/O, A/O, A/A), regulatory MBL2 promoter polymorphism in position -221 (XX, XY, YY), anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), disease activity by Disease Activity Score-28 (DAS28 score), physical disability by Health Assessment Questionnaire (HAQ) score, and erosive changes in hands and feet (Sharp-van der Heijde score)., Results: Eight patients were homozygous MBL2 defective (O/O), 101 belonged to an intermediate group, and 49 were MBL2 high producers (YA/YA). Anti-CCP was present in 93 patients (59%). High scores of disease activity, C-reactive protein-based DAS28 (p=0.02), and physical disability by HAQ (p=0.01) were associated with high MBL2 expression genotypes in a gene-dose dependent way, but only in anti-CCP-positive patients. At this early stage of the disease there was no association with erosion score from radiographs., Conclusion: The results point to a synovitis-enhancing effect of MBL in anti-CCP-positive RA, whereas such an effect was not demonstrated for joint erosions.

Objectives: To determine the N-terminal propeptide of collagen IIA (PIIANP) in early and established rheumatoid arthritis (RA) and to study the association with collagen II degradation assessed by its C-telopeptide (CTX-II), x-ray status and disease activity measures., Methods: Two cohorts of RA patients were included: A) a one-year prospective cohort including 45 patients with early, untreated RA and B) a cross-sectional study comprising 50 RA patients with advanced disease. Blood donors and healthy volunteers served as controls. PIIANP in serum and urine CTX-II were measured by ELISA., Results: PIIANP did not differ from control levels at any time in patients with early RA (p=0.16 and p=0.89), but at one-year follow-up, PIIANP was decreased compared with baseline (p=0.046). In patients with longstanding RA, PIIANP was lower than in controls (p=0.002) and RA patients with a 12-month disease (p=0.01). PIIANP was unrelated to joint counts and CRP in both cohorts, but baseline PIIANP was lower among x-ray progressors than in non-progressors (p=0.04). CTX-II was persistently increased in both cohorts (p<0.001 and p<0.001). CTX-II was positively associated with joint counts and CRP but not with x-ray progression (p=0.84). There was no correlation between PIIANP and CTX-II., Conclusion: Declining PIIANP with increasing RA duration and persistently increased CTX-II indicate that cartilage anabolic and degradative pathways are unbalanced from clinical RA onset. Furthermore, that collagen II depletion in RA is both mediated by anti-anabolic effects unassociated with synovitis (decreased PIIANP) and by excess collagen II degradation linked to synovitis (increased CTX-II).

Serum YKL-40 is a potential biomarker of prognosis in cancer patients, but assessment of serum YKL-40 requires knowledge of its normal variation. In this study, we evaluated diurnal, weekly, and long-term variation in serum YKL-40 in healthy subjects using a commercial ELISA. The intra-assay coefficient of variation was

Interleukin (IL)-6, a key player in the inflammatory response, may be a useful biomarker in rheumatoid arthritis (RA). The aim was to determine analytical variability, a reference interval in healthy subjects, and long- and short-term variation in serum and plasma IL-6 in healthy subjects and RA patients. An enzyme-linked immunosorbent assay from R&D was used for determination of serum and plasma IL-6. The IL-6 concentration did not depend on the type of anticoagulant used or the 3-h time delay between sampling and processing or repeated freeze-thaw cycles. The median plasma and serum IL-6 in 318 healthy subjects were 1.3 pg ml(-1) (range 0.33-26) and 1.4 pg ml(-1) (range 0.25-23), respectively. The median coefficient of variation in plasma IL-6 in 27 healthy subjects during 1 month, and repeated after 6 and 12 months were 27%, 31% and 26%, respectively. No significant long-term changes were observed in serum IL-6 over a 3-year period (14%, p = 0.33). Exercise (cycling) increased serum IL-6 in healthy subjects but not in RA patients. In conclusion, circulating IL-6 is stable regarding sample handling and shows little variation over time. Changes in IL-6 concentrations > 60% (2 times the biological variation) are likely to reflect changes in disease activity and not only pre-analytical or normal biological variability.

Background: Tissue inhibitor of metalloproteinases-1 (TIMP-1) measurements in plasma may be useful for the early detection and prognosis of colorectal cancer (CRC). Data on analytical performance and normal intra- and interindividual biological variation are required in order to interpret the utility of TIMP-1 in CRC. The aim of this study was to establish the biological and analytical variation of plasma TIMP-1 in volunteers., Material and Methods: Three separate studies were undertaken. 1: Plasma was collected from 23 volunteers 6 times within a 3-week period, first in September 2004 (round [R] 1), then repeated in May 2005 (R2) and May 2006 (R3) in the same group of individuals. TIMP-1 levels were determined by the MAC15 ELISA assay and with the Abbott ARCHITECT i2000 Immunoanalyzer. 2: Circadian variation was evaluated in plasma collected 7 times within a 24-hour period (n=16). 3: Effects of physical exercise were evaluated in plasma collected before and after bicycling (n=14). In studies 2 and 3 TIMP-1 levels were determined with the MAC15 ELISA assay only., Results: A significant correlation between TIMP-1 MAC15 and ARCHITECT i2000 was shown (rs=0.78, p<0.002), with consistently higher levels being detected by the ARCHITECT i2000. Median levels of TIMP-1 (ARCHITECT) at 8 a.m. in each round were 74.9 ng/mL (range 65.7-89.9) (R1), 87.3 ng/mL (range 72.7-127.9) (R2), and 81.9 ng/mL (range 66.8-113.6) (R3). The within-subject variation was 10.7%, the variation between rounds was 7.4%, and the intraclass correlation was 46.2%. Comparison between the 3 rounds and time of collection showed that TIMP-1 values decreased by 11% after storage for more than 16 months (p=0.0002). A systematic circadian variation in plasma TIMP-1 levels was not observed (p=0.17). No significant variation of plasma TIMP-1 was found in relation to physical exercise (p=0.92 [global test])., Conclusion: Levels of plasma TIMP-1 in volunteers show limited circadian, day-to-day, week-to-week and season-to-season variation. In addition, physical exercise has no impact on plasma TIMP-1 levels. Possible storage-dependent decreases in plasma TIMP-1 levels warrant further investigation.

Background: Soluble vascular endothelial growth factor (VEGF) is a promising biomarker in monitoring rheumatoid arthritis (RA), but studies of pre-analytical and biologic variability are few., Methods: VEGF was measured by ELISA methods in serum and plasma from healthy persons and RA patients. Pre-analytical factors were investigated. A reference interval for VEGF was established in serum and plasma from 306 healthy persons. Diurnal, day-to-day, week-to-week, long-term variability, and impact of exercise were evaluated., Results: Delayed processing time, room temperature, low centrifugal force and contamination of plasma with cellular elements lead to significant increases in VEGF levels, whereas storage for up to 2 years at -80 degrees C or up to 10 freeze/thaw cycles did not affect VEGF levels. Serum VEGF levels were 7-10 fold higher than plasma VEGF levels. Reference intervals for VEGF (plasma: 45 pg/ml (range: non-detectable to 352); serum: 328 pg/ml (53-1791)) were independent of gender and age. Short- and long-term biologic variability included diurnal variation (sampling should take place after 7 AM) and impact of exercise (increased VEGF immediately after bicycling normalised within 1 hour)., Conclusions: Pre-analytical factors and biologic variability including diurnal variation and impact of exercise should be accounted for in future studies that include circulating VEGF as a biological marker.

Objective: Several actions of the chemokine CXCL12 have potential relevance for rheumatoid arthritis (RA). Interaction with CXCR4, the unique receptor for CXCL12, stimulates angiogenesis, mononuclear cell trafficking into the joints, lymphoid-tissue-like rearrangement of T cells within the synovium, and chondrocyte release of cartilage-degrading metalloproteinases. We investigated the level of CXCL12 in plasma (p-CXCL12) as a marker of RA diagnosis, RA disease activity, and response to methotrexate (MTX) treatment., Methods: A prospective study including 36 patients with RA (ACR criteria) of at least 6 months' duration, and 50 sex and age matched healthy controls. ELISA for CXCL12 was performed on plasma prior to and after 16 and 28 weeks of MTX treatment in the patients with RA and once in controls., Results: The p-CXCL12 was 1855 +/- 145 pg/ml in RA patients and 1273 +/- 79 pg/ml in controls (p < 0.001). During the 28 weeks of MTX treatment, the ACR disease activity variables decreased, whereas the p-CXCL12 level remained constant and increased. P-CXCL12 was not correlated to any ACR disease activity variable at any time (p > 0.05)., Conclusion: Patients with RA had a significantly and constantly increased p-CXCL12 level compared to controls. The p-CXCL12 level was independent of any ACR disease activity variables, as well as response to MTX treatment.