Phenotypic characteristics of patients with chronic widespread pain and fibromyalgia: a cross-sectional cluster analysis.

OBJECTIVE: This study aimed to explore whether phenotypic characteristics of patients with chronic widespread pain (CWP) and fibromyalgia (FM) can be aggregated into definable clusters that may help to tailor treatments. METHOD: Baseline variables (sex, age, education, marital/employment status, pain duration, prior CWP/FM diagnosis, concomitant rheumatic disease, analgesics, tender point count, and disease variables derived from standardized questionnaires) collected from 1099 patients (93.4% females, mean age 44.6 years) with a confirmed CWP or FM diagnosis were evaluated by hierarchical cluster analysis. The number of clusters was based on coefficients in the agglomeration schedule, supported by dendrograms and silhouette plots. Simple and multiple regression analyses using all variables as independent predictors were used to assess the likelihood of cluster assignment, reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Only one cluster emerged (Cluster 1: 455 patients). Participants in this cluster were characterized as working (OR 66.67, 95% CI 7.14 to 500.00), with a medium-term/higher education (OR 16.80, 95% CI 1.94 to 145.41), married/cohabiting (OR 14.29, 95% CI 1.26 to 166.67), and using mild analgesics (OR 25.64, 95% CI 0.58 to > 999.99). The odds of being an individual in Cluster 1 were lower when having a worse score on the PDQ (score ≥ 18) (OR < 0.001, 95% CI < 0.001 to 0.02). CONCLUSION: We identified one cluster, where participants were characterized by a potentially favourable clinical profile. More studies are needed to evaluate whether these characteristics could be used to guide the management of patients with CWP and FM.

Effectiveness of patient education as a stand-alone intervention for patients with chronic widespread pain and fibromyalgia: a systematic review and meta-analysis of randomized trials.

OBJECTIVE: Patient education is recommended as an integral component of the therapeutic plan for the management of chronic widespread pain (CWP) and fibromyalgia (FM). The key purpose of patient education is to increase the patient's competence to manage his or her own health requirements, encouraging self-management and a return to desired everyday activities and lifestyle. The aim of this systematic review was to evaluate the evidence for the benefits and potential harms associated with the use of patient education as a stand-alone intervention for individuals with CWP and FM through randomized controlled trials (RCTs). METHOD: On 24 November 2021 a systematic search of PubMed, MEDLINE, Embase, CENTRAL, PsycINFO, CINAHL, ClinicalTrials.gov, American College of Rheumatology, European League Against Rheumatism, and the World Health Organization International Clinical Trials Registry Platform identified 2069 studies. After full-text screening, five RCT studies were found to be eligible for the qualitative evidence synthesis. RESULTS: Patient education as a stand-alone intervention presented an improvement in patients' global assessment (standardized mean difference 0.79, 95% confidence interval 0.13 to 1.46). When comparing patient education with usual care, no intervention, or waiting list, no differences were found for functioning, level of pain, emotional distress in regard to anxiety and depression, or pain cognition. CONCLUSION: This review reveals the need for RCTs investigating patient education as a stand-alone intervention for patients with FM, measuring outcomes such as disease acceptance, health-related quality of life, enhancement of patients' knowledge of pain, pain coping skills, and evaluation of prioritized learning outcomes.

Confirmation of an IRAK3 polymorphism as a genetic marker predicting response to anti-TNF treatment in rheumatoid arthritis.

Several genetic variants in Toll-like receptor (TLR) and nuclear factor (NF)-κB signalling pathways have been reported associated with responsiveness to tumour necrosis factor inhibitor (anti-TNF) treatment in rheumatoid arthritis (RA). The present study was undertaken to replicate these findings. In a retrospective case-case study including 1007 Danish anti-TNF-treated RA patients, we genotyped 7 previously reported associated single-nucleotide polymorphisms (SNPs) in these pathways. Furthermore, 5 SNPs previously reported by our group were genotyped in a subcohort (N=469). Primary analyses validated the IRAK3 rs11541076 variant as associated (odds ratio (OR)=1.33, 95% confidence interval (CI): 1.00-1.77, P-value=0.047) with a positive treatment response (EULAR (European League Against Rheumatism) good/moderate vs none response at 4±2 months), and found the NLRP3 rs461266 variant associated (OR=0.75, 95% CI: 0.60-0.94, P=0.014) with a negative treatment response. Meta-analyses combining data from previous studies suggested smaller effect sizes of associations between variant alleles of CHUK rs11591741, NFKBIB rs3136645 and rs9403 and a negative treatment response. In conclusion, this study validates rs11541076 in IRAK3, a negative regulator of TLR signalling, as a predictor of anti-TNF treatment response, and suggests true positive associations of previously reported SNPs within genes encoding activators/inhibitors of NF-κB (CHUK, MYD88, NFKBIB, and NLRP3).

Increased prevalence of autoimmunity in Turner syndrome--influence of age.

Individuals with Turner syndrome (TS) are prone to develop autoimmune conditions such as coeliac disease (CD), thyroiditis and type 1 diabetes (T1DM). The objective of the present study was to examine TS of various karyotypes for autoantibodies and corresponding diseases. This was investigated in a prospective cross-sectional study of Danish TS patients (n = 107, median age 36.7 years, range: 6-60 years). A medical history was recorded and a blood sample was analysed for autoantibodies against gliadin, transglutaminase, adrenal cortex, intrinsic factor, anti-thyroid peroxidase (anti-TPO) and glutamic-acid-decarboxylase 65 (GAD-65). Autoantibodies were present in 58% (n = 61) of all patients, whereof 18% (11) had autoantibodies targeting more than one organ. Patients with autoantibodies were significantly older than those without (P = 0.001). Anti-TPO was present in 45% (48) of patients, of whom 33% (16) were hypothyroid. Overall, 18% (19) presented with CD autoantibodies, of whom 26% (five) had CD. Anti-TPO and CD autoantibodies co-existed in 9% (10). Immunoglobulin A deficiency was found in 3% (three) of patients, who all had CD autoantibodies without disease. Among four patients with anti-GAD-65 none had T1DM, but two were classified as having T2DM. One patient had adrenocortical autoantibodies but not adrenal failure. Autoantibodies against intrinsic factor were absent. Anti-GAD-65 was increased in isochromosomal karyotypes (3/23 versus 1/84, P = 0.008) with no other association found between autoantibodies and karyotype. In conclusion, TS girls and women face a high prevalence of autoimmunity and associated disease with a preponderance towards hypothyroidism and CD. Thus, health care providers dealing with this patient group should be observant and test liberally for these conditions even before clinical symptoms emerge.

Clinical optimization and multicenter validation of antigen-specific cut-off values on the INNO-LIA ANA update for the detection of autoantibodies in connective tissue disorders.

OBJECTIVES: The INNO-LIA ANA Update is a qualitative multiparameter line immunoassay for detection of autoantibodies to several different antigens associated with connective tissue disorders. We sought to optimize and validate the cut-off values for its antigen-specific components: SmB, SmD, RNP-70k, RNP-A, RNP-C, SSA/Ro52, SSA/Ro60, SSB/La, Cenp-B, Topo-I, Jo-1, ribosomal P, and histones. Our aim was to achieve 98% specificity for each of the markers, with respect to differential disease controls, while maintaining sensitivity. METHODS: For optimization, the cut-off value of the different antigen lines was fixed to achieve this specificity using an in-house set of 955 patient samples. Specificity was validated at multiple sites using a different set of 330 samples obtained from 158 apparently healthy blood donors, 100 patients with a variety of infections, 20 each with Wegener's granulomatosis, inflammatory bowel disease, and primary antiphospholipid syndrome, and 12 with psoriatic arthritis. Sensitivity was evaluated, using this optimized cut-off control, in 147 patients with scleroderma, 93 with Sjögren's disease, 40 with systemic lupus erythematosus, 40 with rheumatoid arthritis, 39 with mixed connective tissue disease, and 19 with polymyositis. Sensitivity and specificity of the INNO-LIA ANA Update were determined using the clinical diagnosis as reference. RESULTS: The optimized cut-off values resulted in a specificity 98% or more for all LIA markers except one (histones 97.8%) in the validation set of 330 samples. The sensitivity for each marker tested in 378 samples from the target patient groups was comparable to that reported in the literature. CONCLUSION: The INNO-LIA ANA Update shows uniformly high specificities combined with sensitivities very similar to those of reference assays, in a single test format.

Reactive arthritis and serum levels of mannose binding lectin -- lack of association.

The purpose was to evaluate the possible association of serum mannose binding lectin (s-MBL) levels on type of triggering microbe, duration of diarrhoea, incidence and course of reactive arthritis (ReA) caused by Salmonella, Yersinia and Campylobacter. Sixty patients with ReA of 1-228 months duration, 173 patients with ReA or uncomplicated enterocolitis caused by Campylobacter, 226 sera from patients with elevated antibody levels against Salmonella, Yersinia or Campylobacter, and 114 blood donors were tested for s-MBL using ELISA technique, both direct mannan binding assay and sandwich ELISA. s-MBL was compared with C-reactive protein (CRP) levels and with the ability of activating complement C4. Among the 114 donors 9% had s-MBL <50 microg/l, 16% had from 50-500 microg/l and 75% had >500 microg/l. The distribution of s-MBL levels in the three-patient groups did not differ significantly from the controls. There were no indications that low s-MBL was associated with prolonged duration of arthritis, diarrhoea or individual bacterial infections. The two MBL assays were comparable with respect to serum concentrations, indicating that the actual circulating MBL was also functionally active. s-MBL exhibited acute phase reactant behaviour and correlated to CRP level, but only in patients with s-MBL concentrations exceeding 1000 microg/l. MBL in 10 randomly selected ReA sera were tested for the ability to activate complement C4. The results did not differ from those of donor controls. This study demonstrates that the distributions of s-MBL levels in serum among patients with ReA are not different from donor controls. The course, outcome or triggering bacteria are not associated with a particular level of s-MBL.

Comparison of rheumatological and gastrointestinal symptoms after infection with Campylobacter jejuni/coli and enterotoxigenic Escherichia coli.

OBJECTIVES: To estimate the incidence of postinfectious joint complaints after Campylobacter jejuni/coli enteritis compared with enteritis caused by enterotoxigenic E coli (ETEC). To compare gastrointestinal symptoms, antibiotic treatment, and antibody levels among patients with and without joint symptoms. METHOD: Questionnaires were sent to 210 consecutive patients with Campylobacter infection and an equal number of patients with E coli (ETEC). Blood samples for anti-Campylobacter antibodies were collected after two weeks, three months, six months, and two years. RESULTS: Twenty seven of 173 (16%) patients with Campylobacter and 10/177 (6%) with E coli (ETEC) reported joint symptoms (p=0.004). In the Campylobacter group duration of diarrhoea was a median of 13 days for patients with arthralgia and seven days for those without joint pain (p=0.0058). Patients with E coli had diarrhoea of longer duration than patients infected with Campylobacter (14 days v seven days; p=0.0005). E coli patients had fewer gastrointestinal symptoms than Campylobacter patients (p=0.0001). Fifty nine per cent of Campylobacter patients with joint pain had received antibiotic treatment because of enteritis compared with 26% with enteritis only (p=0.03). Campylobacter species and serotypes were equally distributed in both groups and there was no difference in anti-Campylobacter antibody levels between the groups. CONCLUSION: There was a significantly increased risk of developing joint symptoms after contracting Campylobacter infection compared with E coli. Campylobacter patients with joint pain had more severe gastrointestinal symptoms and longer duration of diarrhoea. Antibiotic treatment does not seem to prevent reactive joint symptoms. Levels of anti-Campylobacter antibodies were the same in both groups.

Characterisation of autoantibodies to neutrophil granule constituents among patients with reactive arthritis, rheumatoid arthritis, and ulcerative colitis.

OBJECTIVE: To study the frequency and distribution of antineutrophil cytoplasmic autoantibodies (ANCA) among patients with reactive arthritis (ReA), rheumatoid arthritis (RA), and ulcerative colitis (UC) using different immunological methods. METHODS: Fifty serum samples from patients with reactive arthritis (26 with acute disease and 24 with chronic disease-that is disease of more than one year) were analysed for ANCA with indirect immunofluorescence, enzyme linked immunosorbent assay (ELISA) with six different neutrophil granule proteins as antigens, and immunoblotting on whole neutrophil extract and extracts of azurophil and specific granules. Thirty serum samples from patients with RA and UC served as controls in ELISA and indirect immunofluorescence. RESULTS: Sixteen per cent of patients with ReA were positive in immunofluorescence compared with 30% of patients with RA, and 70% of patients with UC. Thirty two per cent of patients with ReA were positive in ELISA. Antibodies directed against lactoferrin occurred in 20%, antibodies against bactericidal permeability increasing protein (BPI), elastase, cathepsin G, myeloperoxidase, and proteinase 3 were found in 8%, 2%, 2%, 8%, and 6%, respectively. Overall, 50% of RA sera and 53% of UC sera were positive in one or more ELISA assays, the corresponding figures for antibodies against individual antigens were for RA 7%, 3%, 0%, 13%, 47%, 17% and for UC 13%, 20%, 0%, 23%, 10%, and 17%. In immunoblotting, bands corresponding to lactoferrin and BPI were recognised in 44% and 22% of ReA sera. CONCLUSION: Antibodies against neutrophil granule antigens are often found in patients with ReA, primarily among those with chronic disease. The different methods detect various subsets of antibodies, with immunoblotting being the most and immunofluorescence the least sensitive.

Arthritis as presenting symptom in silent adult coeliac disease. Two cases and review of the literature.

We report 2 cases of adult silent coeliac disease (CD) presenting with arthritis of a knee and a sacro-iliac joint, respectively. In both patients the arthritis was relieved on a gluten free diet. The literature on arthritis in adult CD is reviewed.

Anti-lactoferrin antibodies and other types of anti-neutrophil cytoplasmic antibodies (ANCA) in reactive arthritis and ankylosing spondylitis.

Fifty-five serum samples from patients with reactive arthritis (ReA), 40 from patients with ankylosing spondylitis (AS) and three from patients with chronic sacroiliac joint arthritis were analysed for the presence of ANCA of IgG class by means of enzyme immunosorbent assay using lactoferrin (Lf), myeloperoxidase (MPO) and antigen extracted from azurophil granules ('alpha-antigen') containing proteinase 3 (PR3) as substrate. IgG-ANCA were found in 31 (56%) patients with ReA. Twenty-three (42%) had anti-Lf antibodies, nine (16%) had anti-MPO and eight (15%) had anti-alpha-antigen antibodies, none of which reacted with PR3. Only six (14%) AS or sacroiliac joint arthritis patients had ANCA (P < 0.001). Three (7%) had anti-Lf, two (5%) anti-MPO and two (5%) anti-alpha-antigen antibodies. Yersinia and Salmonella bacteria were separated by SDS-PAGE and blots were incubated with serum from rabbits immunized with human Lf. The hyperimmune serum recognized a band of 78 kD from both bacteria which was not seen when preimmune serum was used. The reaction to the 78-kD antigen could be completely inhibited when anti-Lf antibodies were absorbed on Lf coupled to cyanogen bromide-activated Sepharose, possibly indicating cross-reacting epitopes in Lf and enterobacterial antigen.

Soluble urokinase plasminogen activator receptor in plasma of patients with inflammatory rheumatic disorders: increased concentrations in rheumatoid arthritis.

OBJECTIVE: Urokinase type plasminogen activator (uPA) catalyses the formation of the proteolytic enzyme plasmin, which is involved in matrix degradation in the processes of tissue remodelling. Because of a surface bound uPA receptor (uPAR), expressed by some cell types (for example, macrophages, malignant cells and inflammatory activated synoviocytes), the action of uPA can be localised and intensified. uPAR seems to have a role in the mechanisms leading to invasive growth of malignant tissue and the rheumatoid pannus. uPAR may become cleaved at its cell surface anchor, thus forming a free soluble receptor (suPAR). suPAR is detectable in low but constant values in plasma of healthy people, while increased concentrations are found in patients with disseminated malignant disease, so that suPAR may be an indicator of invasive growth and tissue remodelling. suPAR concentrations in plasma have not previously been measured in rheumatic patients. A controlled cross sectional measurement was performed of suPAR in plasma of patients with various inflammatory rheumatic disorders with special reference to rheumatoid arthritis (RA). METHODS: suPAR in plasma was measured by ELISA technique in patients with RA (n=51), reactive arthritis (ReA) (n=23), primary Sjögren's syndrome (PSS) (n=42) and sex and age matched healthy controls (n=53). RESULTS: In the control group suPAR (median) was 0. 91 (range 0.56-1.94) microg/l. Median suPAR value in RA was 1.47 (range 0.65-6.62) microgram/l; in ReA 0.68 microgram/l (range 0.52-1.48) and in PSS 1.12 microgram/l (range 0.76-1.92); p versus controls <0.001 in all patient groups. suPAR values in RA were also significantly increased compared with ReA (p<0.001) and PSS (p=0.004) groups. suPAR in RA was positively correlated to C reactive protein (CRP) (p<0.01) and erythrocyte sedimentation rate (p<0.05) and number of swollen joints (p<0.05). The ReA group had the highest CRP values of all groups, but at the same time the lowest suPAR concentrations in plasma. CONCLUSIONS: Increased suPAR concentrations were found in plasma in RA, and to a smaller extent also in PSS, but not in ReA. In RA suPAR is related to disease activity. suPAR seems though not merely to be an acute phase reactant like CRP. Increased suPAR values might reflect erosive activity in RA.

Antineutrophil cytoplasmic antibodies in reactive arthritis.

OBJECTIVE: To study the occurrence of antineutrophil cytoplasmic antibodies (ANCA) in reactive arthritis (ReA). METHODS: Sera from 22 patients with ReA were analyzed by ELISA for the presence of autoantibodies (IgG and IgA) against a proteinase-3 containing azurophilic granule extract ("alpha-antigen") from human polymorphonuclear leukocytes, myeloperoxidase (MPO), and lactoferrin (Lf), respectively. Rheumatoid factor (RF), antinuclear antibodies (ANA), and HLA-B27 were also tested. Erythrocyte sedimentation rate and serum levels of C-reactive protein were used to assess disease activity. The patients were divided into acute or chronic (> 1 year) disease. RESULTS: 12/22 patients (55%) had IgG ANCA (7 had MPO ANCA, 8 had Lf ANCA, and 4 had alpha-ANCA). Eight patients (36%) had IgA ANCA. One serum was positive only for IgA ANCA. 18/21 patients (86%) were HLA-B27 positive, and none had RF or ANA. The triggering infection was Chlamydia trachomatis in 6 cases. Campylobacter jejuni in 6, Yersinia enterocolitica in 4. In 6 patients the causative microorganism could not be determined. ANCA was more prevalent in chronic disease (6/7, 82%) compared to acute (7/15, 47%). No obvious correlation was seen between ANCA and disease activity. CONCLUSION: ANCA, predominantly those reacting with Lf and/or MPO preparations, are common in ReA.

Reactive arthritis after Salmonella among medical doctors--study of an outbreak.

OBJECTIVE: To investigate an outbreak of S. enteritidis enterocolitis which occurred at a radiology symposium in Malmö, Sweden in March, 1990. METHODS: Questionnaires were mailed to the 126 participants after 1 and 6 months inquiring about enterocolitis, joint and eye symptoms and antibiotic treatment. Fifty-one delivered blood samples for serological studies. RESULTS: One hundred thirteen responded to the questionnaire. Enterocolitis was reported by 108 individuals (96%) and 17 (15%) developed reactive arthritis (ReA). Only 3 persons reported conjunctivitis. Antibody response did not differ between patients with uncomplicated enterocolitis or ReA. IgA antibodies had the highest sensitivity to detect infected individuals. Ten out of 65 patients treated with antibiotics (mean 9.1 days) for enterocolitis and 7 out of 48 nontreated reported joint symptoms. At 6 month followup 8 patients had persistent joint complaints. CONCLUSION: Following an outbreak of S. enteritidis dysentery, joint symptoms may be more frequent than previously thought and could not be prevented by early antibiotic treatment. Nor did antibiotics affect the duration of ReA over a 6 month followup period.

Severe skin necrosis following warfarin therapy in a patient with protein C deficiency.

A female patient with a history of both arterial and venous thrombosis developed extensive skin necrosis following warfarin treatment. When protein C deficiency was diagnosed, successful anticoagulation with warfarin was achieved by prolonging the course of intravenous heparin and introducing warfarin therapy with a low initial dose which was gradually increased. Aspects of the pathogenic mechanism are discussed.

Improved prognosis of ovarian cancer in The Netherlands during the period 1975-1985: a registry-based study.

Survival of 568 patients with ovarian cancer, diagnosed in 1975-1985, was studied by means of a population-based registry in the Southeast Netherlands. Patients diagnosed in the period 1981-1985 had a significantly better prognosis than patients diagnosed in 1975-1980. This improvement of survival declined with advancing age of the patients. In women younger than 60 years, mortality from ovarian cancer decreased, while incidence remained stable. Apart from the effect of new treatment methods, consisting of more extensive tumor reduction and cisplatin-based combination chemotherapy, advances in supportive care as well as a trend toward earlier diagnosis, possibly in combination with an increasing proportion of less malignant tumors, may explain the improvement in prognosis. Survival was strongly related to stage at diagnosis and to age, the prognosis of younger patients being more favorable. Patients with tumors of either germ cell or stromal origin generally survived longer than patients with epithelial tumors, but this difference disappeared after adjustment for stage and age. Patients still alive after 6 years did not have a survival significantly different from that of the general female population.

Large vessel occlusion, cerebral infarction and thrombocytopenia in the "primary" antiphospholipid syndrome. Response to anticoagulation.

A 65-year-old white female without lupus developed concurrent thrombocytopenia and disturbed arterial circulation to the brain and lower leg (a minor stroke and lower leg gangrene, necessitating amputation). Laboratory studies disclosed high levels of anticardiolipin antibodies. Anticoagulant treatment restored circulation in the remaining leg and also normalized platelet levels. This case emphasizes the importance of searching for anticardiolipin antibodies in unexplained thrombotic events.

Wegener's granulomatosis: treatment failure on conventional therapy.

We report a patient with Wegener's granulomatosis who was initially stabilized, but later relapsed with multiorgan involvement while taking high oral doses of cyclophosphamide (3.7 mg/kg body weight/day) and prednisolone. Remission was achieved with a combined therapy consisting of intermittent intravenous boluses of cyclophosphamide, oral prednisolone, plasmapheresis and oral trimethoprim-sulfamethoxazole. Discussion includes evaluation of the relative beneficial effect of the four treatment constituents.