Impact of Manual Addition of Vancomycin to Polymethylmethacrylate (PMMA) Cements.

(1) Background: The addition of antibiotics to bone cements is a common practice in the treatment of periprosthetic joint infections. In revision cases, the amount and type of antibiotic is often insufficient and additional antibiotics must be added. The addition, however, changes the product itself, and the surgeon becomes the "manufacturer" of the bone cement. PMMAe wished to clarify whether the admixture of antibiotics changes the mechanical stability of the bone cements used and if the added antibiotics were still functional and released in sufficient quantities. (2) Methods: We compared two industrially manufactured vancomycin-containing PMMA cements; the low-viscous VancogenX® (TECRES, Sommacampagna, Italy) and the high-viscous Copal® G+V (Heraeus Medical GmbH, Wehrheim, Germany), with two PMMA cements loaded with aminoglycosides, to which 2.0 g of vancomycin (Hexal CT1631) were manually added-the high-viscous Smartset® GHV and the medium-viscous Antibiotic Simplex with Tobramycin (antibiotic Simplex® T). Test specimens of the bone cements were used to determine mechanical stability (bending strength and bending module), and the release of the antibiotics was determined by HLPC and modified Kirby-Bauer assays. (3) Results: All tested bone cements showed an initial high release within the first hours. Repeated testing after 24 h showed a reduced efficacy of VancogenX® and Smartset® GHV in Kirby-Bauer assays. Long-time release over days showed a release of functional antimicrobial active ingredients over this period of time in anti-microbial assays, but no activity of VancogenX® from day 21 onward. No significant differences in the ISO bending modules could be detected, but in contrast to the bending module, the ISO bending strength was substantially reduced by 10-15 mPal in comparison to both cements of the reference group. The Simplex®T met just the ISO 5833; the Smartset® GHV did not after adding vancomycin. (4) Conclusions: In conclusion, the manual addition of 2 g of vancomycin to 40 g of PMMA powder is recommended for the treatment of methicillin-resistant staphylococci. Vancomycin is released over a period of 42 days with concentrations above the MIC for typical staphylococci. The mechanical properties of the PMMA just met, or did not fulfill, ISO mechanical specification. Copal® G+V showed a better elution than VancogenX® over time.

Evaluation of Gentamicin Release of PMMA Cements Using Different Methods: HPLC, Elution and Inhibition Zone Testing.

(1) Background: There is an ongoing discussion on the elution efficacy of antibiotic-impregnated cements. Our experiments were intended to clarify if there are differences in the antibiotic elution of HPLC compared with inhibition zone testing using eluates or PMMA discs. (2) Materials and Methods: Two cement brands with different concentrations of the active ingredient were tested in antimicrobial Kirby-Bauer (disc diffusion) assays. Cement platelets were directly applied on the agar plates and their zone of inhibition was measured. In parallel, the platelets were incubated in phosphate buffered saline (PBS) and at distinct points of time transferred into new buffer. At these time points, 50 µL of the bone cement eluates was used for zone of inhibition testing. Standard gentamicin sulfate solutions served as a control in the same test setup. To verify the microbiological investigations, the antibiotic content of the eluates was also measured via high-performance liquid chromatography (HPLC). (3) Results: The experiments with cement eluates showed better differentiable results than the direct application of the cement discs. The results were also comparable to investigations with HPLC and gentamicin sulfate standard solutions. (4) Conclusions: The results of elution rates are influenced by the test system and the period of observation chosen. The microbial test systems reflect the results of HPLC to the same degree and give evidence of the efficacy of the antibiotics. The HPLC tests on eluates were more suitable in representing differences in release characteristics.

Does the Addition of Low-Dose Antibiotics Compromise the Mechanical Properties of Polymethylmethacrylate (PMMA)?

The increasing numbers of total joint replacements and related implant-associated infections demand solutions, which can provide a high-dose local delivery of antibiotics. Antibiotic-loaded bone cement (ALBC) is an accepted treatment method for infected joint arthroplasties. The mechanical properties of low-dose gentamicin-loaded bone cement (BC) in medium- and high-viscosity versions were compared to unloaded BC using a vacuum mixing system. As an additional control group, manual mixed unloaded BC was used. In a uniaxial compression test, ultimate compressive strength, compressive yield strength, and compression modulus of elasticity, as well as ultimate and yield strain, were determined according to ISO 5833-2022 guidelines. All groups exceeded the minimum compressive strength (70 MPa) specified in the ISO 5833 guidelines. Both ALBC groups showed a similar ultimate compressive and yield strength to the unloaded BC. The results showed that vacuum mixing increased the compression strength of BC. ALBC showed similar compressive strength to their non-antibiotic counterparts when vacuum mixing was performed. Added low-dose gentamicin acted as a plasticizer on bone cement. From a biomechanical point of view, the usage of gentamicin-based ALBC formulations is viable.

Evidence for cemented TKA and THA based on a comparison of international register data.

BACKGROUND: Hip and knee implants can either be fixed without cement, press-fit, or with bone cement. Real-world data from arthroplasty registers, as well as studies provide a broad database for the discussion of cemented versus uncemented arthroplasty procedures. OBJECTIVE: What does current evidence from international arthroplasty registries and meta-analyses recommend regarding cemented or cementless fixation of hip and knee implants? METHODS: A recommendation is generated by means of direct data comparison from the arthroplasty registries of eight countries (USA, Germany, Australia, UK, Sweden, Norway, New Zealand, Netherlands), the comparison of 22 review studies and meta-analyses based on registry data, as well as an evaluation of recommendations of healthcare systems from different nations. For this purpose, reviews and meta-analyses were selected where the results were statistically significant, as were the annual reports of the arthroplasty registries that were current at the time of writing. RESULTS: For knee arthroplasties, long survival time as well as lower risk of revision can be achieved with the support of cemented fixation with antibiotic-loaded bone cement. In patients aged 70 years and older, cemented fixation of hip stem implants significantly reduces risk of intraoperative or postoperative periprosthetic fracture (quadruple). This applies both to elective total hip arthroplasties and to hemiarthroplasty after femoral neck fractures. Antibiotic-loaded bone cement significantly (p = 0.041) reduces the risk of periprosthetic infection, especially in patients with femoral neck fractures. CONCLUSION: Total knee replacement with antibiotic-loaded bone cement is well established internationally and is evidence-based. Registry data and meta-analyses recommend cemented fixation of the hip stem in older patients. In Germany, USA and Australia these evidence-based recommendations still must be transferred to daily practice.

Prospective study validating a multidimensional treatment decision score predicting the 24-month outcome in untreated patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, the ProVal-MS study.

INTRODUCTION: In Multiple Sclerosis (MS), patients´ characteristics and (bio)markers that reliably predict the individual disease prognosis at disease onset are lacking. Cohort studies allow a close follow-up of MS histories and a thorough phenotyping of patients. Therefore, a multicenter cohort study was initiated to implement a wide spectrum of data and (bio)markers in newly diagnosed patients. METHODS: ProVal-MS (Prospective study to validate a multidimensional decision score that predicts treatment outcome at 24 months in untreated patients with clinically isolated syndrome or early Relapsing-Remitting-MS) is a prospective cohort study in patients with clinically isolated syndrome (CIS) or Relapsing-Remitting (RR)-MS (McDonald 2017 criteria), diagnosed within the last two years, conducted at five academic centers in Southern Germany. The collection of clinical, laboratory, imaging, and paraclinical data as well as biosamples is harmonized across centers. The primary goal is to validate (discrimination and calibration) the previously published DIFUTURE MS-Treatment Decision score (MS-TDS). The score supports clinical decision-making regarding the options of early (within 6 months after study baseline) platform medication (Interferon beta, glatiramer acetate, dimethyl/diroximel fumarate, teriflunomide), or no immediate treatment (> 6 months after baseline) of patients with early RR-MS and CIS by predicting the probability of new or enlarging lesions in cerebral magnetic resonance images (MRIs) between 6 and 24 months. Further objectives are refining the MS-TDS score and providing data to identify new markers reflecting disease course and severity. The project also provides a technical evaluation of the ProVal-MS cohort within the IT-infrastructure of the DIFUTURE consortium (Data Integration for Future Medicine) and assesses the efficacy of the data sharing techniques developed. PERSPECTIVE: Clinical cohorts provide the infrastructure to discover and to validate relevant disease-specific findings. A successful validation of the MS-TDS will add a new clinical decision tool to the armamentarium of practicing MS neurologists from which newly diagnosed MS patients may take advantage. Trial registration ProVal-MS has been registered in the German Clinical Trials Register, `Deutsches Register Klinischer Studien` (DRKS)-ID: DRKS00014034, date of registration: 21 December 2018; https://drks.de/search/en/trial/DRKS00014034.

[Register data on cemented arthroplasty : A proof for cementless fixation?] / Registerdaten zur zementierten Endoprothetik : Belegen sie den Trend zur zementfreien Versorgung?

BACKGROUND: Hip and knee implants can be either fixated without cement, press-fit, or with bone cement. Real-world data from arthroplasty registers, as well as studies, provide a broad database for the discussion of cemented versus uncemented arthroplasty procedures. OBJECTIVES: What is the recommendation for cemented or cementless anchorage of hip and knee implants based on the current evidence from international arthroplasty registries and meta-analyses? METHODS: A recommendation is generated by means of a direct comparison of data from the arthroplasty registries of eight different countries (USA, Germany, Australia, UK, Sweden, Norway, New Zealand, and The Netherlands), the comparison of 22 review studies and meta-analyses based on registry data, as well as the evaluation of the recommendation of healthcare systems of different nations. For this purpose, reviews and meta-analyses whose results were statistically significant were selected, as were the annual reports of the arthroplasty registries that were current at the time of writing. RESULTS: For knee endoprostheses, a long survival time, as well as a lower risk of revision can be achieved with the help of cemented anchorage with antibiotic-laden bone cement. In patients aged 70 years and older, cemented anchorage of the hip stem implant significantly reduces the risk of intraoperative or postoperative periprosthetic fracture (times four), this applies both to elective total hip arthroplasties (TEPs) and to hemiarthroplasty after femoral neck fractures. Antibiotic-loaded bone cement significantly (p = 0.041) reduces the risk of periprosthetic infection, especially in patients with femoral neck fractures. CONCLUSIONS: Total knee replacement with antibiotic-loaded bone cement is well established in Germany and evidence based. Registry data and meta-analyses recommend cemented fixation of the hip stem in older patients-in Germany the evidence-based recommendations must still be transferred to daily practice.

[Cement in revision arthroplasty-what about the "glacier effect"? : Case studies viewed from different perspectives]. / Zement in der Revisionsendoprothetik ­ Was ist mit dem "Gletschereffekt"? : Fallbeispiele aus unterschiedlichen Perspektiven betrachtet.

BACKGROUND: The number of operations concerning revision arthroplasty has been increasing continuously in recent years, and it can be assumed that they will continue to increase in the future. If an arthroplasty implant becomes loose, it must be changed. The question often arises as to how the new implant should be fixed in the bone. ADVANTAGES: Revision implants can be inserted into the bone without cement. In the subsequent period, a secondary osseointegration of the implant takes place. Another possibility is to anchor the implant by using bone cement. The advantage of cemented anchorage is that the implant is firmly fixed in the bone, in principle, immediately, and it is possible to fully load the implant directly. Direct postoperative full weight bearing is helpful, especially for older and multimorbid patients, in order to achieve rapid mobilization. PREREQUISITES AND CHALLENGES: When using cement in revision cases, however, there are a few prerequisites and challenges that the surgeon should definitely take into account. In the case of revision, the bone in the former implant bed is often deficient and appears thinned and sclerosed. It is, therefore, important to analyze the bone quality preoperatively on radiographic images and to include it in the planning of the anchoring strategy. In addition, the individual bone quality of the patient must also be taken into account intraoperatively. In any case, it must be clarified whether the basic prerequisites for the sufficient bond strength of the cement with the bone to be formed can still be met. Furthermore, the principles of cementing technique must be strictly observed, and the goal of a perfect cement mantle must be aimed for. If the indication for this is overstated, early loosening of the cemented revision arthroplasty is very likely.

Daptomycin-Impregnated PMMA Cement against Vancomycin-Resistant Germs: Dosage, Handling, Elution, Mechanical Stability, and Effectiveness.

BACKGROUND: The number of periprosthetic joint infections caused by vancomycin-resistant pathogens is increasing. Currently, no PMMA cement is commercially available to cover VRE. Daptomycin shows promising results in treating infection, offering a good safety profile and a reduced risk of developing resistance. The purpose of this in vitro study was to investigate the mechanical stability, handling properties, elution behavior, and antimicrobial effectiveness of PMMA cement loaded with three different daptomycin concentrations in comparison to commercially available antibiotic-loaded bone cement (ALBC). METHODS: Mechanical properties and handling characteristics (ISO 5833, DIN 53435), HPLC elution, antimicrobial effectiveness with proliferation assay (DIN 17025), and inhibition zone testing were investigated. RESULTS: All tested daptomycin concentrations met the ISO and DIN standards for mechanical strength. Loading of 40 g of PMMA cement with 0.5 g of daptomycin did not show any antimicrobial effectiveness, in contrast to 1.0 g and 1.5 g. PMMA cement with 1.5 g of daptomycin was the best in terms of elution and effectiveness, and it showed good ISO mechanical strength; ISO doughing was sticky for a little longer and setting was faster compared to the vancomycin-containing reference cement. CONCLUSION: PMMA cement containing 0.5 g of gentamicin and 1.5 g of daptomycin could be a good alternative to the already established COPAL® (Wehrheim, Germany) G+V for the treatment of PJIs caused by VRE.

[Processing properties and viscosities of PMMA bone cements]. / Verarbeitungseigenschaften und Viskositäten von PMMA-Knochenzementen.

Processing properties of PMMA bone cements can be divided into four phases: 1. mixing, 2. waiting, 3. processing and 4. curing. Each of these phases is subject to several external influencing factors, such as temperature and humidity, which must be considered during application. Instructions for use provided by the manufacturers of PMMA bone cements and mixing and application systems contain important information on correct application. The processing properties of PMMA bone cements and possible factors influencing the curing process are of great importance for safe procedures in the operating room. Knowledge of the viscosity and consistency of the PMMA bone cement from the dough phase to complete curing facilitates preparation and application, which in the long term significantly improves the requirements placed on PMMA cements regarding the function and service life of the implant.

[The third-generation modern cementing technique in hip and knee arthroplasty]. / Moderne Zementiertechnik der dritten Generation in der Knie- und Hüftendoprothetik.

BACKGROUND: Implant loosening is the most common reason for revision surgery. OBJECTIVES: Contribution of modern cementing technique to the long-term stability of an implant. METHODS: Evaluation of the available evidence on modern cementing technique. RESULTS: Modern cementing technique in hip arthroplasty is considered established and leads to better cementing results. In knee arthroplasty, there are also specific recommendations, including intensive cleaning of the bone bed, mixing of bone cement under vacuum and application of bone cement to the implant and the bone. CONCLUSIONS: The use of modern cementing technique in hip and knee arthroplasty facilitates cementing, increases safety, and minimizes the risk of mechanical loosening.

[Chemical and physical properties of PMMA bone cements]. / Chemische und physikalische Eigenschaften von PMMA-Knochenzementen.

PMMA-based bone cements are used for anchoring artificial joints. The cements are offered as two-component systems. During mixing, a liquid paste is formed by free-radical polymerization, which completely hardens into a solid cement matrix as polymerization progresses with an increase in viscosity. Polymerization from MMA to PMMA is an exothermic process, energy is released in the form of heat. After fixation of the prosthesis and curing of the cement, the cement fills the space between the prosthesis and the bone. With the filler PMMA, a strong force-locking and interlocking mechanical bond is created. The essential properties of PMMA cements are dictated by the powder component. In vivo, the hard and brittle bone cements absorb body fluids and become more elastic and softer. The properties of various PMMA bone cements differ significantly, although the chemical acrylate base is identical.

[Bone cement as a local antibiotic carrier]. / Knochenzement als lokaler Antibiotikaträger.

BACKGROUND: There is widespread consensus that adjuvant local use of antimicrobial agents in combination with their systemic administration can better prevent and treat implant-associated musculoskeletal infections. The advantage of local antibiotics lies in their particular pharmacokinetics with initially high antibiotic concentrations at the implant site with only low systemic uptake. AIM OF TREATMENT: The aim of local application is to protect the foreign bodies directly at the implantation site from bacterial colonization and biofilm formation (prophylaxis) and to support the eradication of an already established infection after surgical debridement (treatment). Since the observations of Prof. Buchholz, bone cement has been the most frequently used local carrier system. APPLICATION: In cases of infection, surgeons should ideally work together with microbiologists, infectiologists or clinical pharmacists to determine which anti-infective agents are indicated systemically for the patient and which ones are indicated locally with PMMA cement, based on the pathogen(s) and antibiograms. However, for the anti-infective agents administered with bone cement, there is still uncertainty about which agents can be added to this carrier material and at what concentrations. Accordingly, the authors of this review article not only summarize the rationale and evidence for local antibiotic use but also elaborate on the points that must be considered for admixing these agents to the cement.

Micromotion measurement at the interfaces of cemented tibial endoprosthetic replacements: A new standardized in vitro model using open-cell rigid foam.

Early aseptic loosening following primary total knee arthroplasty related to several factors might appear at the interface implant-cement or cement-bone. A standardized in vitro model might provide information on the relevance of single variable parameter of cementation including technique and cement respectively bone structure on fixation strength. Micromotion measurement using different directions of load should detect the primary stability of the interfaces. An open-cell rigid foam model was used for cementation of PFC-Sigma tibial trays with Palacos®. Pins were applied to the model for continuous non-destructive measurement. Relative micromotions for rotation, valgus-varus and extension flexion stress were detected at the interfaces as well as cement penetration was measured. The reproducibility of the measurement could be shown for all interfaces in extension-flexion movements. For rotation a negative trend was shown for the interface cement-prosthesis and cement-bone concerning varus-valgus stress reflecting varying surgical cementation technique. More micromotion related to extension-flexion force might reflect the design of the implant. Measurement of relative micromotion and cement distribution appear accurate to detect small differences of movement at different interfaces of cemented tibial implants and the results are reproducible for most parameter. An increased number of specimens should achieve statistical relevance for all measurements.

Voriconazole Admixed with PMMA-Impact on Mechanical Properties and Efficacy.

BACKGROUND: There are currently no recommendations to direct the optimal diagnosis and treatment of fungal osteoarticular infections, including prosthetic joint infections and osteomyelitis. Active agents (fluconazole; amphotericin B) are regularly applied per os or intravenously. Other drugs such as voriconazole are used less frequently, especially locally. Voriconazole is less toxic and has promising results. Local antifungal medication during primary surgical treatment has been investigated by implanting an impregnated PMMA cement spacer using intra-articular powder or by daily intra-articular lavage. The admixed dosages are rarely based on characteristic values and microbiological and mechanical data. The purpose of this in vitro study is to investigate the mechanical stability and efficacy of antifungal-admixed PMMA with admixed voriconazole at low and high concentrations. METHODS: Mechanical properties (ISO 5833 and DIN 53435) as well as efficacy with inhibition zone tests with two Candida spp. were investigated. We tested three separate cement bodies at each measuring time (n = 3) Results: Mixing high dosages of voriconazole causes white specks on inhomogeneous cement surfaces. ISO compression, ISO bending, and DIN impact were significantly reduced, and ISO bending modulus increased. There was a high efficacy against C. albicans with low and high voriconazole concentrations. Against C. glabrata, a high concentration of voriconazole was significantly more efficient than a dose at a low concentration. CONCLUSIONS: Mixing voriconazole powder with PMMA (Polymethylmethacrylate) powder homogeneously is not easy because of the high amount of dry voriconazole in the powder formulation. Adding voriconazole (a powder for infusion solutions) has a high impact on its mechanical properties. Efficacy is already good at low concentrations.

Retrospective cohort study to devise a treatment decision score predicting adverse 24-month radiological activity in early multiple sclerosis.

Background: Multiple sclerosis (MS) is a chronic neuroinflammatory disease affecting about 2.8 million people worldwide. Disease course after the most common diagnoses of relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) is highly variable and cannot be reliably predicted. This impairs early personalized treatment decisions. Objectives: The main objective of this study was to algorithmically support clinical decision-making regarding the options of early platform medication or no immediate treatment of patients with early RRMS and CIS. Design: Retrospective monocentric cohort study within the Data Integration for Future Medicine (DIFUTURE) Consortium. Methods: Multiple data sources of routine clinical, imaging and laboratory data derived from a large and deeply characterized cohort of patients with MS were integrated to conduct a retrospective study to create and internally validate a treatment decision score [Multiple Sclerosis Treatment Decision Score (MS-TDS)] through model-based random forests (RFs). The MS-TDS predicts the probability of no new or enlarging lesions in cerebral magnetic resonance images (cMRIs) between 6 and 24 months after the first cMRI. Results: Data from 65 predictors collected for 475 patients between 2008 and 2017 were included. No medication and platform medication were administered to 277 (58.3%) and 198 (41.7%) patients. The MS-TDS predicted individual outcomes with a cross-validated area under the receiver operating characteristics curve (AUROC) of 0.624. The respective RF prediction model provides patient-specific MS-TDS and probabilities of treatment success. The latter may increase by 5-20% for half of the patients if the treatment considered superior by the MS-TDS is used. Conclusion: Routine clinical data from multiple sources can be successfully integrated to build prediction models to support treatment decision-making. In this study, the resulting MS-TDS estimates individualized treatment success probabilities that can identify patients who benefit from early platform medication. External validation of the MS-TDS is required, and a prospective study is currently being conducted. In addition, the clinical relevance of the MS-TDS needs to be established.

PREDICT-juvenile-stroke: PRospective evaluation of a prediction score determining individual clinical outcome three months after ischemic stroke in young adults - a study protocol.

BACKGROUND: Although of high individual and socioeconomic relevance, a reliable prediction model for the prognosis of juvenile stroke (18-55 years) is missing. Therefore, the study presented in this protocol aims to prospectively validate the discriminatory power of a prediction score for the 3 months functional outcome after juvenile stroke or transient ischemic attack (TIA) that has been derived from an independent retrospective study using standard clinical workup data. METHODS: PREDICT-Juvenile-Stroke is a multi-centre (n = 4) prospective observational cohort study collecting standard clinical workup data and data on treatment success at 3 months after acute ischemic stroke or TIA that aims to validate a new prediction score for juvenile stroke. The prediction score has been developed upon single center retrospective analysis of 340 juvenile stroke patients. The score determines the patient's individual probability for treatment success defined by a modified Rankin Scale (mRS) 0-2 or return to pre-stroke baseline mRS 3 months after stroke or TIA. This probability will be compared to the observed clinical outcome at 3 months using the area under the receiver operating characteristic curve. The primary endpoint is to validate the clinical potential of the new prediction score for a favourable outcome 3 months after juvenile stroke or TIA. Secondary outcomes are to determine to what extent predictive factors in juvenile stroke or TIA patients differ from those in older patients and to determine the predictive accuracy of the juvenile stroke prediction score on other clinical and paraclinical endpoints. A minimum of 430 juvenile patients (< 55 years) with acute ischemic stroke or TIA, and the same number of older patients will be enrolled for the prospective validation study. DISCUSSION: The juvenile stroke prediction score has the potential to enable personalisation of counselling, provision of appropriate information regarding the prognosis and identification of patients who benefit from specific treatments. TRIAL REGISTRATION: The study has been registered at https://drks.de on March 31, 2022 ( DRKS00024407 ).

Association of pregnancies with risk of multiple sclerosis.

BACKGROUND: Pregnancies have an impact on the disease course of multiple sclerosis (MS), but their relationship with MS risk is yet unclear. OBJECTIVE: To determine the relationships of pregnancies and gynecological diagnoses with MS risk. METHODS: In this retrospective case-control study, we assessed differences in gynecological International Classification of Diseases, 10th Revision (ICD-10) code recording rates between women with MS (n = 5720), Crohn's disease (n = 6280), or psoriasis (n = 40,555) and women without these autoimmune diseases (n = 26,729) in the 5 years before diagnosis. RESULTS: Twenty-eight ICD-10 codes were recorded less frequently for women with MS as compared to women without autoimmune disease, 18 of which are pregnancy-related. After adjustment for pregnancies, all codes unrelated to pregnancies were still negatively associated with MS. In a sensitivity analysis excluding women with evidence for possible demyelinating events before diagnosis, all associations were more pronounced. In comparison to women with psoriasis, most associations could be confirmed; that was not true in comparison to women with Crohn's disease. CONCLUSION: Our findings provide evidence for a possible protective effect of pregnancies on MS risk likely independent of or in addition to a previously suggested reversed causality. The negative associations of gynecological disorders with disease risk need further investigation. The associations might be shared by different autoimmune diseases.