Association Between Autoimmune Diseases and Monoclonal Gammopathy of Undetermined Significance : An Analysis From a Population-Based Screening Study.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. In previous registry-based, retrospective studies, autoimmune diseases have been associated with MGUS. However, these studies were not based on a screened population and are therefore prone to ascertainment bias. OBJECTIVE: To examine whether MGUS is associated with autoimmune diseases. DESIGN: A cross-sectional study within iStopMM (Iceland Screens, Treats, or Prevents MM), a prospective, population-based screening study of MGUS. SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 75 422 persons screened for MGUS. MEASUREMENTS: Poisson regression for prevalence ratios (PRs) of MGUS among persons with or without an autoimmune disease, adjusted for age and sex. RESULTS: A total of 10 818 participants had an autoimmune disorder, of whom 599 had MGUS (61 with a prior clinical diagnosis and 538 diagnosed at study screening or evaluation). A diagnosis of an autoimmune disease was not associated with MGUS (PR, 1.05 [95% CI, 0.97 to 1.15]). However, autoimmune disease diagnoses were associated with a prior clinical diagnosis of MGUS (PR, 2.11 [CI, 1.64 to 2.70]). LIMITATION: Registry data were used to gather information on autoimmune diseases, and the homogeneity of the Icelandic population may limit the generalizability of these results. CONCLUSION: The study did not find an association between autoimmune disease and MGUS in a systematically screened population. Previous studies not done in systematically screened populations have likely been subject to ascertainment bias. The findings indicate that recommendations to routinely screen patients with autoimmune disease for MGUS may not be warranted. PRIMARY FUNDING SOURCE: The International Myeloma Foundation and the European Research Council.

Drug effectiveness of 2nd and 3rd TNF inhibitors in psoriatic arthritis - relationship with the reason for withdrawal from the previous treatment.

OBJECTIVE: To investigate real-world retention and remission rates in PsA patients initiating a 2nd or 3rd TNFi and the association with reason for discontinuation from the previous TNFi-treatment. METHODS: Prospectively collected routine care data from 12 European registries were pooled. Retention rates (Kaplan-Meier estimation) and crude/LUNDEX-adjusted rates of Disease Activity Score 28 and Disease Activity index for PSoriatic Arthritis (DAS28 and DAPSA28) remission were calculated and compared with adjusted Cox regression analyses and Chi-squared test, respectively). RESULTS: We included 5233 (2nd TNFi) and 1906 (3rd TNFi) patients. Twelve-month retention rates for the 2nd and 3rd TNFi were 68% (95%CI: 67-70%) and 66% (64-68%), respectively. Patients who stopped the previous TNFi due to AE/LOE had 12-month retention rates of 66%/65% (2nd TNFi), and 65%/63% (3rd TNFi), respectively. Patients who stopped the previous TNFi due to LOE after less vs more than 24 weeks had 12-month retention rates of 54%/69% (2nd TNFi), and 58%/65% (3rd TNFi). Six-month crude/LUNDEX-adjusted DAS28 remission rates were 48%/35% and 38%/27%, and DAPSA28 remission rates were 19%/14% and 14%/10%, for the 2nd and 3rd TNFi. CONCLUSION: Two-thirds of patients remained on TNFi at 12months for both the 2nd and 3rd TNFi, while one-third and one-quarter of patients were in DAS28 remission after 6months on the 2nd and 3rd TNFi. While drug effectiveness was similar in patients who stopped the previous TNFi due to AE compared to overall LOE, drug effectiveness was better in patients who had stopped the previous TNF due to secondary LOE compared to primary LOE.

Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance : A Cohort Study Nested in a Clinical Trial.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management. OBJECTIVE: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model. DESIGN: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597). SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. MEASUREMENTS: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater. RESULTS: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds. LIMITATION: The prediction model will require external validation. CONCLUSION: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology. PRIMARY FUNDING SOURCE: International Myeloma Foundation and the European Research Council.

Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden.

There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with higher prevalence or increased progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore present a target population for MGUS screening. This two-part study is the first study to evaluate the relationship of MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio (OR)= 1.10; 95% confidence interval (CI): 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer associated with the progression of MGUS, except for myeloid malignancies which were associated with lower risk of progression (hazard ratio (HR)=0.37; 95%CI: 0.16-0.89; p=0.028). Our findings indicate that a prior cancer are not a significant aetiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer.

Predictors of DAPSA28 remission in patients with psoriatic arthritis initiating a first TNF inhibitor: results from 13 European registries.

OBJECTIVES: In bio-naïve patients with PsA initiating a TNF inhibitor (TNFi), we aimed to identify baseline predictors of Disease Activity index for PsA in 28 joints (DAPSA28) remission (primary objective) and DAPSA28 moderate response at 6 months, as well as drug retention at 12 months across 13 European registries. METHODS: Baseline demographic and clinical characteristics were retrieved and the three outcomes investigated per registry and in pooled data, using logistic regression analyses on multiply imputed data. In the pooled cohort, selected predictors that were either consistently positive or negative across all three outcomes were defined as common predictors. RESULTS: In the pooled cohort (n = 13 369), 6-month proportions of remission, moderate response and 12-month drug retention were 25%, 34% and 63% in patients with available data (n = 6954, n = 5275 and n = 13 369, respectively). Five common baseline predictors of remission, moderate response and 12-month drug retention were identified across all three outcomes. The odds ratios (95% CIs) for DAPSA28 remission were: age, per year: 0.97 (0.96-0.98); disease duration, years (<2 years as reference): 2-3 years: 1.20 (0.89-1.60), 4-9 years: 1.42 (1.09-1.84), ≥10 years: 1.66 (1.26-2.20); men vs women: 1.85 (1.54-2.23); CRP of >10 vs ≤10 mg/l: 1.52 (1.22-1.89) and 1 mm increase in patient fatigue score: 0.99 (0.98-0.99). CONCLUSION: Baseline predictors of remission, response and adherence to TNFi therapy were identified, of which five were common for all three outcomes, indicating that the predictors emerging from our pooled cohort may be considered generalizable from country level to disease level.

Long COVID in Icelandic Children: A Matched Cohort Study of Nonspecific Symptoms Following SARS-CoV-2 Infection.

PURPOSE: Pediatric severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections are usually mild and the mortality rates are low, but concerns have been raised about long-term symptoms that may resemble other postinfectious syndromes. Studies with robust control groups and high response rates have been few. METHODS: We obtained identifiers for all 837 Icelandic children diagnosed with SARS-CoV-2 by PCR between March 2020 and June 2021 and contacted them by telephone. We asked about 10 physical and mental symptoms being present at least twice weekly for at least 2 months. Participants who reported symptoms were contacted again a year later. For each subject who completed the questionnaire, an age- and sex-matched comparator without SARS-CoV-2 infection was asked to complete the same questionnaire, and the risk difference was calculated. RESULTS: Responses from 643 cases and 602 comparators were analyzed. Children who had been infected with SARS-CoV-2 were more likely to report one or more symptoms, except for anxiety/depression and sleep disturbances. Fatigue and loss of concentration were evidently more common in cases among teenagers (risk difference: 15%; 95% CI: 7-22% and 15%; 95% CI: 7-23%, respectively). At the second follow-up, close to a third of Long COVID cases had resolved but some participants had developed new persistent symptoms. CONCLUSION: Symptoms of Long COVID in children are common and impact their quality of life. The importance of further unraveling the pathophysiology of acute and long-term symptoms following SARS-CoV-2 infection in children is vital as well as potential preventive measures.

Trends of perceived disruption in healthcare services during the pandemic: findings from the COVID-19 National Resilience Cohort in Iceland.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused major disruptions in healthcare services worldwide. Yet, little is known about the association between perceived disruption in healthcare services and socio-demographic factors, pre-existing health conditions as well as concurrent physical and psychological symptoms. METHODS: Leveraging data from the Icelandic COVID-19 National Resilience Cohort, we performed a repeated measure analysis among 15 754 participants who responded to the question on perceived disruption in healthcare services from December 2020 to July 2021, to explore its association with socio-demographic factors, health indicators and conditions. Furthermore, we performed a longitudinal analysis among 7848 participants with two repeated measures to explore the association between timing and duration of perceived disruption in healthcare services and changes in depression, anxiety, sleep quality and somatic symptoms. RESULTS: The prevalence of perceived disruption in healthcare services slightly decreased over time (P < 0.01). Perceived disruption in healthcare services was more prevalent among individuals with pre-existing health conditions, i.e. history of psychiatric disorders (prevalence ratio = 1.59, 95% confidence interval 1.48-1.72) and chronic somatic conditions [1.40 (1.30-1.52)]. However, no increase in the prevalence of perceived disruption in healthcare services was observed among individuals diagnosed with COVID-19 [0.99 (0.84-1.18)]. Moreover, we found that emerging perceived disruption in healthcare services was associated with an increase in symptoms of mental illness during the pandemic (ßs 0.06-0.68). CONCLUSIONS: A disruption in healthcare services during the COVID-19 pandemic was reported by vulnerable groups, while the Icelandic healthcare system managed to maintain accessible services to individuals with COVID-19.

Determining hemodilution in diagnostic bone marrow aspirated samples in plasma cell disorders by next-generation flow cytometry: Proposal for a bone marrow quality index.

Hemodilution of bone marrow (BM) aspirates is a limitation of multiparameter flow cytometry (MFC) in plasma cell disorders. There is a need for a validated approach for assessing sample quality and the distribution of non-plasma cell BM populations by MFC could provide a solution. We evaluated BM-associated cell populations, assessed by next-generation flow cytometry (NGF) and white blood cell (WBC) count in 351 BM aspirated samples from 219 participants with plasma cell disorders in the Iceland Screens, Treats, or Prevents MM study (iStopMM), as markers of hemodilution by their discriminatory ability between first and (generally more hemodiluted) second pull BM aspirated samples. The most discriminating markers were used to derive a novel BM quality index (BMQI). Nucleated red blood cells and myeloid precursors provided the greatest discriminatory ability between first vs second pull samples (area under the curve (AUC): 0.87 and 0.85, respectively), significantly better than B cell precursors (AUC = 0.64; p < 0.001), mast cells (AUC = 0.65; p < 0.001), and the BM WBC count (AUC = 0.77; p < 0.05). We generated a novel BMQI that is intrinsic to current NGF protocols, for evaluating quality of diagnostic BM samples and suggest the use of a BMQI scoring system for interpreting results and guiding appropriate actions.

Immunophenotypic assessment of clonal plasma cells and B-cells in bone marrow and blood in the diagnostic classification of early stage monoclonal gammopathies: an iSTOPMM study.

Monoclonal gammopathy of undetermined significance (MGUS) is the earliest discernible stage of multiple myeloma (MM) and Waldenström's macroglobulinemia (WM). Early diagnosis of MG may be compromised by the low-level infiltration, undetectable to low-sensitive methodologies. Here, we investigated the prevalence and immunophenotypic profile of clonal (c) plasma cells (PC) and/or cB-lymphocytes in bone marrow (BM) and blood of subjects with a serum M-component from the iSTOPMM program, using high-sensitive next-generation flow cytometry (NGF), and its utility in the diagnostic classification of early-stage MG. We studied 164 paired BM and blood samples from 82 subjects, focusing the analysis on: 55 MGUS, 12 smoldering MM (SMM) and 8 smoldering WM (SWM). cPC were detected in 84% of the BM samples and cB-lymphocytes in 45%, coexisting in 39% of cases. In 29% of patients, the phenotypic features of cPC and/or cB-lymphocytes allowed a more accurate disease classification, including: 19/55 (35%) MGUS, 1/12 (8%) SMM and 2/8 (25%) SWM. Blood samples were informative in 49% of the BM-positive cases. We demonstrated the utility of NGF for a more accurate diagnostic classification of early-stage MG.

Commonalities and differences in set-up and data collection across European spondyloarthritis registries - results from the EuroSpA collaboration.

BACKGROUND: In European axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) clinical registries, we aimed to investigate commonalities and differences in (1) set-up, clinical data collection; (2) data availability and completeness; and (3) wording, recall period, and scale used for selected patient-reported outcome measures (PROMs). METHODS: Data was obtained as part of the EuroSpA Research Collaboration Network and consisted of (1) an online survey and follow-up interview, (2) upload of real-world data, and (3) selected PROMs included in the online survey. RESULTS: Fifteen registries participated, contributing 33,948 patients (axSpA: 21,330 (63%), PsA: 12,618 (37%)). The reported coverage of eligible patients ranged from 0.5 to 100%. Information on age, sex, biological/targeted synthetic disease-modifying anti-rheumatic drug treatment, disease duration, and C-reactive protein was available in all registries with data completeness between 85% and 100%. All PROMs (Bath Ankylosing Spondylitis Disease Activity and Functional Indices, Health Assessment Questionnaire, and patient global, pain and fatigue assessments) were more complete after 2015 (68-86%) compared to prior (50-79%). Patient global, pain and fatigue assessments showed heterogeneity between registries in terms of wording, recall periods, and scale. CONCLUSION: Important heterogeneity in registry design and data collection across fifteen European axSpA and PsA registries was observed. Several core measures were widely available, and an increase in data completeness of PROMs in recent years was identified. This study might serve as a basis for examining how differences in data collection across registries may impact the results of collaborative research in the future.

Disease associations with monoclonal gammopathy of undetermined significance can only be evaluated using screened cohorts: results from the population-based iStopMM study.

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor condition that precedes multiple myeloma and related disorders but has also been associated with other medical conditions. Since systematic screening is not recommended, MGUS is typically diagnosed due to underlying diseases and most cases are not diagnosed. Most previous studies on MGUS disease associations have been based on clinical cohorts, possibly resulting in selection bias. Here we estimate this selection bias by comparing clinically diagnosed and screened individuals with MGUS with regards to demographics, laboratory features, and comorbidities. A total of 75,422 participants in the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study were screened for MGUS by serum protein electrophoresis, immunofixation and free light chain assay (clinicaltrials gov. Identifier: NCT03327597). We identified 3,352 individuals with MGUS, whereof 240 had previously been clinically diagnosed (clinical MGUS), and crosslinked our data with large, nationwide registries for information on comorbidities. Those with clinical MGUS were more likely to have at least one comorbidity (odds ratio=2.24; 95% confidence interval: 1.30-4.19), and on average had more comorbidities than the screened MGUS group (3.23 vs. 2.36, mean difference 0.68; 95% confidence interval: 0.46-0.90). They were also more likely to have rheumatological disease, neurological disease, chronic kidney disease, liver disease, heart failure, or endocrine disorders. These findings indicate that individuals with clinical MGUS have more comorbidities than the general MGUS population and that previous studies have been affected by significant selection bias. Our findings highlight the importance of screening data when studying biological and epidemiological implications of MGUS.

Uptake and effectiveness of newer biologic and targeted synthetic disease-modifying antirheumatic drugs in psoriatic arthritis: results from five Nordic biologics registries.

BACKGROUND: We aimed to describe the uptake of newer biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in psoriatic arthritis (PsA) in the Nordic countries and to compare their retention and effectiveness. METHODS: Patients with PsA starting a b/tsDMARD in 2012-2020 in five Nordic rheumatology registers were included. Uptake and patient characteristics were described, with comorbidities identified from linkages to national patient registries. One-year retention and 6-month effectiveness (proportions achieving low disease activity (LDA) on the Disease Activity Index for PSoriatic Arthritis based on 28-joint evaluation) for the newer b/tsDMARDs (abatacept/apremilast/ixekizumab/secukinumab/tofacitinib/ustekinumab) were compared with adalimumab through adjusted regression models stratified by treatment course (first, second/third, and fourth or more). RESULTS: In total, 5659 treatment courses with adalimumab (56% biologic-naïve) and 4767 courses with a newer b/tsDMARD (21% biologic-naïve) were included. The uptake of newer b/tsDMARDs increased from 2014 and plateaued in 2018. Patient characteristics appeared similar across treatments at treatment start. Adalimumab was more often used as the first course and newer b/tsDMARDs more often in biologic-experienced patients. Used as a second/third b/tsDMARD, the retention rate and the proportion achieving LDA were significantly better for adalimumab (rate 65%, proportion 59%) compared with abatacept (45%, 37%), apremilast (43%, 35%), ixekizumab (LDA only, 40%) and ustekinumab (LDA only, 40%), but not significantly different from other b/tsDMARDs. CONCLUSION: Uptake of newer b/tsDMARDs occurred mainly in biologic-experienced patients. Regardless of mode of action, only a minority of patients starting a second or later b/tsDMARD course remained on drug and achieved LDA. Superior outcomes for adalimumab indicate that the positioning of newer b/tsDMARDs in the PsA treatment algorithm remains to be established.

Management of Nail Disease in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE: Nail psoriasis is common, impairs fine motor finger functioning, affects cosmesis, and is associated with a lower quality of life. This review updates the previous Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for nail psoriasis. METHODS: This systematic literature review of the PubMed, MEDLINE, Embase, and Cochrane databases examined the updated evidence since the last GRAPPA nail psoriasis treatment recommendations published in 2014. Recommendations are based on preformed PICO (Patient/Population - Intervention - Comparison/Comparator - Outcome) questions formulated by an international group of dermatologists, rheumatologists, and patient panel members. Data from this literature review were evaluated in line with Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. RESULTS: Overall, there is insufficient evidence to make any recommendation for the use of topical corticosteroids, topical calcipotriol, topical tazarotene, topical cyclosporine, dimethyl fumarates/fumaric acid esters, phototherapy, and alitretinoin. There is a low strength of evidence to support the use of calcipotriol and corticosteroid preparations, topical tacrolimus, oral cyclosporine, oral methotrexate, intralesional corticosteroids, pulsed dye laser, acitretin, Janus kinase inhibitors, and apremilast. CONCLUSION: The highest strength of supporting evidence is for the recommendation of biologic agents including tumor necrosis factor inhibitors, and interleukin 12/23, 17, and 23 inhibitors.

Validity of chronic disease diagnoses in Icelandic healthcare registries.

AIMS: To evaluate the validity of recorded chronic disease diagnoses in Icelandic healthcare registries. METHODS: Eight different chronic diseases from multiple sub-specialties of medicine were validated with respect to accuracy, but not to timeliness. For each disease, 30 patients with a recorded diagnosis and 30 patients without the same diagnosis were randomly selected from >80,000 participants in the iStopMM trial, which includes 54% of the Icelandic population born before 1976. Each case was validated by chart review by physicians using predefined criteria. RESULTS: The overall accuracy of the chronic disease diagnoses was 96% (95% CI 94-97%), ranging from 92 to 98% for individual diseases. After weighting for disease prevalence, the accuracy was estimated to be 98.5%. The overall positive predictive value (PPV) of chronic disease diagnosis was 93% (95% CI 89-96%) and the overall negative predictive value (NPV) was 99% (95% CI 96-100%). There were disease-specific differences in validity, most notably multiple sclerosis, where the PPV was 83%. Other disorders had PPVs between 93 and 97%. The NPV of most disorders was 100%, except for hypertension and heart failure, where it was 97 and 93%, respectively. Those who had the registered chronic disease had objective findings of disease in 96% of cases. CONCLUSIONS: When determining the presence of chronic disease, diagnosis data from the Icelandic healthcare registries has a high PPV, NPV and accuracy. Furthermore, most diagnoses can be confirmed by objective findings such as imaging or blood testing. These findings can inform the interpretation of studies using diagnostic data from the Icelandic healthcare registries.

Strong site-specific association of pharyngeal cultures with the onset of psoriatic arthritis and psoriasis, regardless of pathogen.

OBJECTIVES: The objective of this study was to evaluate any association between culture site / culture result / pathogen and incident PsA or psoriasis. METHODS: Records of all samples sent for culture from a large population during a 3-year period were linked with nationwide registry data on diagnoses and death over a 15-year period. The main outcomes of interest were incident diagnoses of PsA and psoriasis, defined by International Classification of Diseases (ICD) codes. The effect of culture site, culture result (positive vs negative), and pathogen (Streptococcus vs negative culture) on the risk of developing PsA and psoriasis was calculated using Cox proportional hazards models adjusted for age and gender. RESULTS: A total of 313 235 bacterial cultures from 128 982 individuals were analysed. Comparing individuals with pharyngeal cultures to those with urine cultures, the hazard ratio for incident PsA was 8.78 [95% confidence interval (CI) 3.23, 23.91] and for incident psoriasis it was 8.00 (95% CI 5.28, 12.12). Most of the risk was concentrated in the first 50 days after the culture date. Increased risk was also found when comparing individuals with cultures from the pharynx with those with cultures from the nasopharynx and blood. An association with streptococci was not found, neither in the pharynx nor at any other site. A positive bacterial culture from any site was associated with reduced risk for both PsA and psoriasis. CONCLUSION: There is a strong site-specific association between pharyngeal culture samples and an increased risk of PsA and psoriasis, regardless of the pathogen. This may indicate that the site of infection, rather than the pathogen, is associated with increased risk.

Haematological malignancies in patients with psoriatic arthritis overall and treated with TNF inhibitors: a Nordic cohort study.

OBJECTIVES: To evaluate the risk of haematological malignancies in patients with psoriatic arthritis (PsA) overall, and in relation to treatment with tumour necrosis factor inhibitors (TNFi). METHODS: We identified that patients with PsA starting a first TNFi from the clinical rheumatology registers (CRR) in the five Nordic countries (n=10 621) and biologics-naïve PsA patients from (1) the CRR (n=18 705) and (2) the national patient registers (NPR, n=27 286, Sweden and Denmark) from 2006 through 2019. For Sweden and Denmark, general population comparators were matched 5:1 to PsA patients on birth year, year at start of follow-up and sex. By linkage to the national cancer registers in all countries, we collected information on haematological malignancies overall, and categorised into lymphoid or myeloid types. We estimated incidence rate ratios (IRRs) with 95% CIs using modified Poisson regression for TNFi-treated versus biologics-naïve PsA patients and versus the general population adjusted for age, sex, calendar period and country. RESULTS: During 59 827 person-years, 40 haematological malignancies occurred among TNFi-treated patients with PsA resulting in a pooled IRR of 0.96 (0.68-1.35) versus biologics-naïve PsA from CRR and an IRR of 0.84 (0.64-1.10) versus biologics-naïve PsA from NPR. The IRR of haematological malignancies in PsA overall versus general population comparators was 1.35 (1.17-1.55). The estimates were largely similar for lymphoid and myeloid malignancies. CONCLUSIONS: Treatment with TNFi in patients with PsA was not associated with an increased incidence of haematological malignancies. Conversely, a moderately increased underlying risk was seen in patients with PsA compared with the general population.

Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: Results of the iStopMM study.

Serum free light chain (FLC) concentration is greatly affected by kidney function. Using a large prospective population-based cohort, we aimed to establish a reference interval for FLCs in persons with chronic kidney disease (CKD). A total of 75422 participants of the iStopMM study were screened with serum FLC, serum protein electrophoresis and immunofixation. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine. Central 99% reference intervals were determined, and 95% confidence intervals calculated. Included were 6461 (12%) participants with measured FLCs, eGFR < 60 mL/min/1.73 m2, not receiving renal replacement therapy, and without evidence of monoclonality. Using current reference intervals, 60% and 21% had kappa and lambda FLC values outside the normal range. The FLC ratio was outside standard reference interval (0.26-1.65) in 9% of participants and outside current kidney reference interval (0.37-3.10) in 0.7%. New reference intervals for FLC and FLC ratio were established. New reference intervals for the FLC ratio were 0.46-2.62, 0.48-3.38, and 0.54-3.30 for eGFR 45-59, 30-44, and < 30 mL/min/1.73 m2 groups, respectively. The crude prevalence of LC-MGUS in CKD patients was 0.5%. We conclude that current reference intervals for FLC and FLC ratio are inaccurate in CKD patients and propose new eGFR based reference intervals to be implemented.

Autoimmunity, Infections, and the Risk of Monoclonal Gammopathy of Undetermined Significance.

Various epidemiological studies, including case reports and -series in addition to larger, population-based studies, have reported an increased prevalence of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma in individuals with a prior history of immune-related conditions. This is believed to support the role of chronic antigen stimulation in the pathogenesis of these conditions. In this short review, we summarize some of the largest population-based studies researching autoimmune diseases, infections, and the subsequent risk of MGUS, and discuss our understanding on its etiology and pathogenesis. Furthermore, we highlight important methodological limitations of previous studies in the field, but almost all studies on MGUS have been based on clinical, possibly biased, cohorts. Finally, we discuss future directions in researching the associations of MGUS and other disorders, including immune-related conditions, where screening studies play an important role.