Does Concomitant Use of Methotrexate with JAK Inhibition Confer Benefit for Cardiovascular Outcomes? A Commentary.

This commentary explores the potential cardiovascular (CV) benefits of combining methotrexate (MTX) and Janus kinase inhibitors (JAKis) in the treatment of rheumatoid arthritis (RA). While European guidelines recommend MTX as first-line treatment, concerns about the CV risks associated with JAKis have emerged. This article reviews the existing literature to assess the role of concomitant MTX in reducing CV risk when used with JAKis. Clinical trials confirm the efficacy of JAKis in combination with MTX in terms of treatment outcomes in RA. However, the number of major adverse cardiovascular events (MACEs) reported is too low to draw conclusions on adverse CV outcomes. Indirect evidence does, however, suggest potential protective effects of MTX on CV outcomes, as several mechanisms may contribute to MTX's cardioprotective effects, including reduced inflammation, adenosine monophosphate-activated protein kinase (AMPK) activation, increased cholesterol efflux, and adenosine accumulation. These mechanisms and the available data may support the case for CV benefits of concomitant MTX when JAKis are used in the treatment of patients with RA, although further research is needed. In particular, the lipid paradox associated with RA highlights the complex relationship between RA treatments (MTX, JAKis, tumor necrosis factor (TNF) inhibitors, and interleukin (IL)-6 receptor inhibitors), inflammation, different lipid profiles, and CV risk. In the absence of contraindications and when MTX is tolerated, this commentary suggests the concomitant use of MTX and JAKis as a preferred option for optimizing CV protection in patients with RA.

JAK inhibitors to treat STAT3 gain-of-function: a single-center report and literature review.

Objective: The signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) syndrome (STAT3-GOF) is an inborn error of immunity (IEI) characterized by diverse manifestations of immune dysregulation that necessitate systemic immunomodulatory treatment. The blockade of the interleukin-6 receptor and/or the inhibition of the Janus kinases has been commonly employed to treat diverse STAT3-GOF-associated manifestations. However, evidence on long-term treatment outcome, especially in the case of adult patients, is scarce. Methods: Clinical data, including laboratory findings and medical imaging, were collected from all seven patients, diagnosed with STAT3-GOF, who have been treated at the Hannover University School, focusing on those who received a Janus kinase (JAK) inhibitor (JAKi). Previously published cases of STAT3-GOF patients who received a JAKi were evaluated, focusing on reported treatment efficacy with respect to diverse STAT3-GOF-associated manifestations of immune dysregulation and safety. Results: Five out of seven patients diagnosed with STAT3-GOF were treated with a JAKi, each for a different indication. Including these patients, outcomes of JAKi treatment have been reported for a total of 41 patients. Treatment with a JAKi led to improvement of diverse autoimmune, inflammatory, or lymphoproliferative manifestations of STAT3-GOF and a therapeutic benefit could be documented for all except two patients. Considering all reported manifestations of immune dysregulation in each patient, complete remission was achieved in 10/41 (24.4%) treated patients. Conclusions: JAKi treatment improved diverse manifestations of immune dysregulation in the majority of STAT3-GOF patients, representing a promising therapeutic approach. Long-term follow-up data are needed to evaluate possible risks of prolonged treatment with a JAKi.

Use of Janus kinase inhibitors before and after European Medicines Agency safety recommendations: a retrospective study.

Background: Safety recommendations for Janus kinase inhibitors (JAKi) issued by the European Medical Agency (EMA) in 2023 could potentially influence treatment patterns for rheumatoid arthritis (RA) drugs, but little is known about the impact of these recommendations in routine clinical care. Methods: We retrospectively analyzed the German RHADAR rheumatology database for adult patients with RA and documentation of a new therapy with a JAKi, tumor necrosis factor inhibitor (TNFi), or interleukin-6 receptor inhibitor (IL-6Ri). Data were grouped into half-yearly intervals from quarter (Q)2/2020 to Q3/2023. The period from Q4/2022 to Q1/2023 immediately followed the initial EMA endorsement of Pharmacovigilance Risk Assessment Committee (PRAC) recommendations and Q2/2023-Q3/2023 immediately followed the direct healthcare provider communication (DHPC) containing the new safety JAKi recommendations. Results: Between April 1, 2020 and September 23, 2023, 3008 newly initiated therapies for TNFi (1499 [49.8%]), JAKi (1126 [37.4%]), and IL-6Ri (383 [12.7%]) were documented by the treating physicians. JAKi were increasingly used in the first two half-year periods (from 29.7% of these therapies in Q2/2020-Q3/2020 to 46.7% in Q2/2021-Q3/2021; odds ratio [OR] 2.08; p<0.001). The proportion of initiated JAKi therapies decreased significantly after the PRAC recommendations (32.9%; OR vs peak 0.56; p=0.001) and the DHPC letter (26.1%; OR vs peak 0.40; p<0.001). JAKi were more likely to be used as >3rd-line therapy in later time periods. Conclusions: This exploratory study suggests that EMA safety recommendations for JAKi influenced treatment patterns of RA patients who received JAKi in Germany. Additional studies will be needed to confirm these findings.

Analysis of the shorter drug survival times for Janus kinase inhibitors and interleukin-17 inhibitors compared with tumor necrosis factor inhibitors in a real-world cohort of axial spondyloarthritis patients - a retrospective analysis from the RHADAR network.

In recent years Janus kinase inhibitors (JAKi) have joined tumor necrosis factor inhibitors (TNFi) and interleukin (IL)-17 inhibitors (IL-17i) as approved disease modifying anti-rheumatic drugs (DMARD) for moderate to severe forms of axial spondyloarthritis (axSpA). Drug survival in axSpA patients has not been well studied in a real-world outpatient scenario since the approval of JAKi. We aimed to analyze the three drug classes based on modes of actions (MoA) for their persistence rates among German axSpA outpatients. A retrospective analysis of the RHADAR database for axSpA patients with a new initiation of TNFi, IL-17i, or JAKi treatment between January 2015 and October 2023 was conducted. Analyses included Kaplan-Meier curves and adjusted Cox regressions for drug discontinuation. 1222 new biological DMARD (TNFi [n = 954], IL-17i [n = 190]) or JAKi (n = 78) treatments were reported. The median drug survival was 31 months for TNFi, 25 for IL-17i, and 18 for JAKi. The corresponding 2-year drug survival rate was 79.6%, 72.6%, and 62.8% for TNFi, IL-17i, and JAKi, respectively. The probability for discontinuation for JAKi was significantly higher compared with TNFi (HR 1.91 [95% CI 1.22-2.99]) as well as for IL-17i compared with TNFi (HR 1.43 [95% CI 1.02-2.01]), possibly related to more frequent use of TNFis as first-line therapy. IL-17i and JAKi discontinuation probabilities were similar. Primary non-response was the reason for drug discontinuation in most cases across all MoA. TNFi treatment might persist longer than JAKi and IL-17i in German axSpA outpatients, possibly related to more severe or refractory disease in patients with JAKi-treated or IL-17i-treated axSpA.

[Head-to-head trials in rheumatoid arthritis]. / Head-to-Head-Therapiestudien zur rheumatoiden Arthritis.

BACKGROUND: Head-to-head studies are important to select the optimal treatment in terms of efficacy and side effect profiles when several drugs are available. AIM OF THE WORK: This article describes all studies comparing the use of disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) in head-to-head studies or in which a DMARD was at least included in an active comparison arm. RESULTS: A total of 23 studies comparing DMARDs were identified. These included comparisons of Janus kinase (JAK) inhibitors with methotrexate and with adalimumab as well as the oral surveillance study. DISCUSSION: There are already an exceptionally large number of head-to-head studies in RA, both for comparisons of efficacy and safety of DMARDs. Nevertheless, more such comparative studies are needed, for example to clarify whether adverse events of tofacitinib observed in the oral surveillance study are specific to the JAK 1/JAK 3 inhibitor or are a class effect of all JAK inhibitors.

Drug survival superiority of tumor necrosis factor inhibitors and interleukin-17 inhibitors over Janus kinase inhibitors and interleukin-12/23 inhibitors in German psoriatic arthritis outpatients: retrospective analysis of the RHADAR database.

Objective: Treatment options with disease-modifying antirheumatic drugs (DMARDs) for psoriatic arthritis (PsA) have evolved over recent years. In addition to Janus kinase inhibitors (JAKi), four classes of biologic DMARDs (bDMARDs; interleukin [IL]-23 inhibitors [IL-23i], IL-12/23 inhibitors [IL-12/23i], tumor necrosis factor inhibitors [TNFi], and IL-17 inhibitors [IL-17i]) are currently approved for moderate to severe PsA treatment. There is minimal evidence of the persistence of these drugs among PsA outpatients in a real-world scenario during the period following the approval of JAKi. Therefore, we aimed to analyze the drug survival rates of biologic and JAKi therapies among German PsA outpatients during routine clinical care. Methods: We retrospectively analyzed PsA patients with a new prescription for a biologic or JAKi in the RHADAR database between January 2015 and October 2023. Kaplan-Meier Curves and Cox regression modelling were used to compare drug survival rates. Results: 1352 new prescriptions with bDMARDs (IL-12/23i [n=50], IL-23i [n=31], TNFi [n=774], IL-17i [n=360]) or JAKi (n=137) were identified. The 5-year drug survival rate was 67.8% for IL-17i, 62.3% for TNFi, 53.3% for JAKi, and 46.0% for IL-12/23i. Discontinuation probabilities for JAKi and IL-12/23i were significantly higher compared with TNFi (JAKi hazard ratio [HR] 1.66, [95% CI 1.23-2.24], p=0.001; IL-12/23i HR 1.54, [95% CI 1.02-2.33], p=0.042) and IL-17i (JAKi HR 1.77, [95% CI 1.27-2.47], p=0.001; IL-12/23i HR 1.64, [95% CI 1.06-2.55], p=0.027). JAKi-treated patients had more severe disease and more osteoarthritis (OA) compared to TNFi and more OA compared to IL-17i. Conclusion: German PsA outpatients might persist longer with TNFi and IL-17i compared with IL-12/23i or JAKi. For TNFi, differences in subgroup characteristics and comorbidities (OA) may have affected drug survival rates. For IL-17i, the longer drug survival might not only be related to less OA compared to JAKi and, therefore, might be affected by other factors.

Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

[Focus on Sjögren's syndrome - Diagnosis and treatment]. / Das Sjögren-Syndrom im Fokus.

In the diagnosis of Sjögren's syndrome the Salivary gland sonography (SGUS) has become established and can lead to a higher specificity of the applicable classification criteria. The OMERACT score is used to objectify the SGUS findings. In laboratory diagnostics, the subspecification of anti-SSA/Ro antibodies, but possibly also new biomarkers, are becoming increasingly important regarding diagnostic safety and the expected manifestations. When it comes to prevention, it has been shown that not only psychological stress, but also cardiovascular risk and the risk of lymphoma allow high-risk patients to be identified more precisely in the future. Using cluster analyses, various phenotype groups could be identified to which clinical parameters could be assigned. In 2020, therapy recommendations were published that are based on the clinical manifestations of SjS and recommend medications that are also used in the treatment of systemic lupus erythematosus (SLE) or rheumatoid arthritis. A particularly large number of therapeutic approaches are dedicated to the B cell: Rituximab and Belimumab have been included in the EULAR recommendations for serious manifestations and Ianalumab has a promising effect. Another focus of current research is the inhibition of co-stimulation between immune cells. After recent disappointing results for Abatacept, clinical trials show promising effects on Iscalimab and Dazodalibep.

[Update on Sjögren's syndrome : Diagnostics, treatment, and challenges]. / Update Sjögren-Syndrom : Diagnostik, Therapie und Fallstricke.

Sjögren's syndrome (SjS) is the most common connective tissue disease with a prevalence of 1:200. Predominantly affecting women, SjS is associated with destruction of the exocrine glands, leading to xerophthalmia and xerostomia. In over 50% of patients, there are also extraglandular manifestations, leading to multiple organ manifestations including polyneuropathies and interstitial lung disease as well as symptoms such as fatigue and arthralgia. Diagnostic procedures include biomarkers, in particular anti-SS-A/Ro antibodies, histology of salivary glands, and salivary gland sonography. There are currently no licensed immunosuppressive drugs for SjS, so current treatment is often based on off-label use of drugs. The European League Against Rheumatism (EULAR) has recently published treatment recommendations based on the prevailing organ manifestations. Several promising controlled trials with novel compounds and concepts are currently in progress.

Treatment strategies in MDA5-positive clinically amyopathic dermatomyositis: a single-center retrospective analysis.

Melanoma differentiation-associated protein 5 (MDA5) antibody positive amyopathic dermatomyositis (DM) is a rare inflammatory disease. So far, there is no official treatment guideline in MDA5 amyopathic dermatomyositis, but early and aggressive immunosuppressive combination treatment can induce a stable remission. We retrospectively analyzed a cohort of eight patients (male n = 5) that were diagnosed with MDA5-positive amyopathic DM. Patient data comprised demographics, CT-guided diagnosis of pulmonary involvement, pulmonary function testing including forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) data on baseline and mean long-term follow-up of 51 months (24-92 months) to evaluate treatment strategies. Depending on severity of organ involvement treatments were individualized including cyclophosphamide, immunoglobulins and plasmapheresis. Simultaneously, oral treatment with tacrolimus was commenced in four of the eight patients. Most patients received remission maintenance therapy with a combination of tacrolimus, rituximab and low dose steroids. In all patients, improvement in FVC was recorded and five patients achieved an improvement in DLCO. An improvement in the CT imaging morphological findings was observed in four patients. Awareness for the entirety of all clinical and disease-related findings of amyopathic DM is crucial, and remission maintenance is often achieved with a combination of tacrolimus and rituximab.

What is the best referral strategy for axial spondyloarthritis? A prospective multicenter study in patients with suspicious chronic low back pain.

OBJECTIVE: To assess the value of referral strategies for axial spondyloarthritis (axSpA) in patients with suspicious chronic inflammatory low back pain (LBP), to estimate the value of inflammatory back pain (IBP) for referral, and to identify the predictive factors of the final diagnosis of axSpA in Middle Eastern Arab countries. METHODS: The study was multicentric, prospective, and conducted in LBP first-line clinics (rheumatology, internal, family medicine, orthopedic surgery, neurosurgery, and neurology). Consecutive adult patients aged under 45years were included in case of LBP suspicious of inflammatory nature according to the first-line physician. The rheumatologist's final diagnosis was the gold standard. The diagnostic properties of ten referral strategies (Brandt I, II, III, Hermann, RADAR, RADAR 2/3, MASTER, Braun, CAFASPA, and ASAS) and of IBP were calculated. A multivariable logistic regression identified the clinical predictive factors of axSpA. RESULTS: In 515 referred patients, axSpA was confirmed in 48%, refuted in 43%, and diagnosis remained inconclusive in 9%. The optimal referral strategy was the MASTER (PLR 3.3), which comprises IBP, good response to NSAIDs, positive HLA-B27, and SpA family history. Considering strategies without HLA-B27, the RADAR 2/3 had a PLR of 2.9 (IBP, good response to NSAIDs, any extra-musculoskeletal manifestation). The predictive factors for axSpA were MRI sacroiliitis, positive HLA-B27, high CRP, psoriasis, IBP, and longer symptom duration. Of all patients, 35% were self-referred, 16% were referred by primary care physicians, and 15% by neuro/orthopedic surgeons. CONCLUSION: Optimizing physicians' awareness of these clinical features may enhance referral in axSpA.

The link between rheumatic disorders and inborn errors of immunity.

Inborn errors of immunity (IEIs) are immunological disorders characterized by variable susceptibility to infections, immune dysregulation and/or malignancies, as a consequence of damaging germline variants in single genes. Though initially identified among patients with unusual, severe or recurrent infections, non-infectious manifestations and especially immune dysregulation in the form of autoimmunity or autoinflammation can be the first or dominant phenotypic aspect of IEIs. An increasing number of IEIs causing autoimmunity or autoinflammation, including rheumatic disease have been reported over the last decade. Despite their rarity, identification of those disorders provided insight into the pathomechanisms of immune dysregulation, which may be relevant for understanding the pathogenesis of systemic rheumatic disorders. In this review, we present novel IEIs primarily causing autoimmunity or autoinflammation along with their pathogenic mechanisms. In addition, we explore the likely pathophysiological and clinical relevance of IEIs in systemic rheumatic disorders.

[Practicable diagnostics of Sjögren's syndrome in interstitial lung disease-A discussion article]. / Praktikable Sjögren-Diagnostik bei interstitieller Lungenerkrankung ­ ein Diskussionsbeitrag.

Sjögren's syndrome (SjS) is a possible autoimmune cause of interstitial lung disease. The diagnostic pathway for SjS, however, is largely undefined in comparison to other systemic autoimmune diseases. Subjective sicca symptoms, anti-SS-A/Ro antibodies and even ANA as screening tests all have relevant limitations in sensitivity and/or specificity. Against this background, in an interdisciplinary discussion we have developed a consensus for the clarification of SjS, which is presented here for broader discussion. In addition to ANA and anti-SS-A/Ro antibodies, antibodies against alpha-fodrin should be included. Objective measures of dryness, such a Schirmer and Saxon tests are important, as is a salivary gland biopsy in the absence of typical autoantibodies.

MPO-ANCA-positive granulomatosis with polyangiitis and concurrent IgG4-related disease with periaortitis and tubulointerstitial nephritis: A case report of a new overlap syndrome?

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that was first recognized as a unique disease entity in the early 2000s. Its diagnosis is based on specific pathologic, serologic, and clinical features, and the exclusion of several differential diagnoses, such antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, emerging evidence suggests that these 2 conditions may overlap in some cases. Here, we report a new case of overlapping IgG4-RD and AAV. The patient was diagnosed with IgG4-RD owing to the presence of periaortitis and IgG4 positive tubulointerstitial nephritis. Myeloperoxidase (MPO)-ANCA positivity, chronic paranasal sinusitis, and glomerulonephritis with granuloma led to a concurrent diagnosis of MPO-ANCA-positive granulomatosis with polyangiitis. Our case supports the hypothesis that diagnoses of IgG4-RD and AAV are not mutually exclusive but can overlap. It can be assumed that an overlap with IgG4-RD typically affects the granulomatous form of AAV, suggesting a common pathophysiological pathway for these 2 conditions.

Baricitinib Safety for Events of Special Interest in Populations at Risk: Analysis from Randomised Trial Data Across Rheumatologic and Dermatologic Indications.

INTRODUCTION: Baricitinib, a Janus kinase (JAK) 1/2 inhibitor, is an approved treatment for rheumatoid arthritis (RA), atopic dermatitis (AD), and alopecia areata (AA). Further characterisation of adverse events of special interest (AESI) for JAK inhibitors in at-risk populations will improve benefit-risk assessment for individual patients and diseases. METHODS: Data were pooled from clinical trials and long-term extensions in moderate-to-severe active RA, moderate-to-severe AD, and severe AA. Incidence rates (IR) per 100 patient-years of major adverse cardiovascular event (MACE), malignancy, venous thromboembolism (VTE), serious infection, and mortality were calculated for patients with low risk (younger than 65 years with no specified risk factors), and patients at risk (≥ 1 of: aged 65 years or older, atherosclerotic cardiovascular disease, diabetes mellitus, hypertension, current smoking, HDL cholesterol < 40 mg/dL, BMI ≥ 30 kg/m2, poor mobility on EQ-5D, or history of malignancy). RESULTS: Datasets included baricitinib exposure up to 9.3 years with 14,744 person-years of exposure (PYE) (RA), 3.9 years with 4628 PYE (AD), and 3.1 years with 1868 PYE (AA). In patients with low risk (RA: 31%, AD: 48%, AA: 49%), IRs for MACE (0.05, 0.04, 0), malignancies (0.20, 0.13, 0), VTE (0.09, 0.04, 0), serious infection (1.73, 1.18, 0.6), and mortality (0.04, 0, 0) in the RA, AD, and AA datasets, respectively, were low. In patients at risk (RA: 69%, AD: 52%, AA: 51%), IRs were for MACE (0.70, 0.25, 0.10), malignancies (1.23, 0.45, 0.31), VTE (0.66, 0.12, 0.10), serious infection (2.95, 2.30, 1.05), and mortality (0.78, 0.16, 0) for RA, AD, and AA datasets, respectively. CONCLUSION: Populations with low risk have low incidence of the examined JAK inhibitor-related AESI. In the dermatologic indications, incidence is also low for patients at risk. Considering individual disease burden, risk factors, and response to treatment is relevant to make informed decisions for individual patients treated with baricitinib.

The efficacy and safety of systemic corticosteroids as first line treatment for granulomatous lymphocytic interstitial lung disease.

BACKGROUND: Granulomatous and lymphocytic interstitial lung disease (gl-ILD) is a major cause of morbidity and mortality among patients with common variable immunodeficiency. Corticosteroids are recommended as first-line treatment for gl-ILD, but evidence for their efficacy is lacking. OBJECTIVES: This study analyzed the effect of high-dose corticosteroids (≥0.3 mg/kg prednisone equivalent) on gl-ILD, measured by high-resolution computed tomography (HRCT) scans, and pulmonary function test (PFT) results. METHODS: Patients who had received high-dose corticosteroids but no other immunosuppressive therapy at the time (n = 56) and who underwent repeated HRCT scanning or PFT (n = 39) during the retrospective and/or prospective phase of the Study of Interstitial Lung Disease in Primary Antibody Deficiency (STILPAD) were included in the analysis. Patients without any immunosuppressive treatment were selected as controls (n = 23). HRCT scans were blinded, randomized, and scored using the Hartman score. Differences between the baseline and follow-up HRCT scans and PFT were analyzed. RESULTS: Treatment with high-dose corticosteroids significantly improved HRCT scores and forced vital capacity. Carbon monoxide diffusion capacity significantly improved in both groups. Of 18 patients, for whom extended follow-up data was available, 13 achieved a long-term, maintenance therapy independent remission. All patients with relapse were retreated with corticosteroids, but only one-fifth of them responded. Two opportunistic infections were found in the corticosteroid treatment group, while overall infection rate was similar between cohorts. CONCLUSIONS: Induction therapy with high-dose corticosteroids improved HRCT scans and PFT results of patients with gl-ILD and achieved long-term remission in 42% of patients. It was not associated with major side effects. Low-dose maintenance therapy provided no benefit and efficacy was poor in relapsing disease.

Targets of autoantibodies in acquired hemophilia A are not restricted to factor VIII: data from the GTH-AH 01/2010 study.

The root cause of autoantibody formation against factor VIII (FVIII) in acquired hemophilia A (AHA) remains unclear. We aimed to assess whether AHA is exclusively associated with autoantibodies toward FVIII or whether patients also produce increased levels of autoantibodies against other targets. A case-control study was performed enrolling patients with AHA and age-matched controls. Human epithelial cell (HEp-2) immunofluorescence was applied to screen for antinuclear (ANA) and anticytoplasmic autoantibodies. Screening for autoantibodies against extractable nuclear antigens was performed by enzyme immunoassay detecting SS-A/Ro, SS-B/La, U1RNP, Scl-70, Jo-1, centromere B, Sm, double-stranded DNA, and α-fodrin (AF). Patients with AHA were more often positive for ANA than control patients (64% vs 30%; odds ratio [OR] 4.02, 1.98-8.18) and had higher ANA titers detected than controls. Cytoplasmic autoantibodies and anti-AF immunoglobulin A autoantibodies were also more frequent in patients with AHA compared with controls. Autoantibodies against any target other than FVIII were found in 78% of patients with AHA compared with 46% of controls (OR 4.16, 1.98-8.39). Results were similar preforming sensitivity analyses (excluding either subjects with autoimmune disorders, cancer, pregnancy, or immunosuppressive medication at baseline) and in multivariable binary logistic regression. To exclude that autoantibody staining was merely a result of cross-reactivity of anti-FVIII autoantibodies, we tested a mix of 7 well-characterized monoclonal anti-FVIII antibodies. These antibodies did not stain HEp-2 cells used for ANA detection. In conclusion, a diverse pattern of autoantibodies is associated with AHA, suggesting that a more general breakdown of immune tolerance might be involved in its pathology.

Anti-CD74 IgA antibodies show diagnostic potential for axial spondyloarthritis but are not associated with microscopic gut inflammation.

OBJECTIVES: Gut inflammation commonly occurs in axial SpA (axSpA), and is linked to disease activity and outcome. Given the role of IgA in mucosal immunity, we explored the association between anti-CD74 IgA antibodies, gut inflammation and axSpA. METHODS: Anti-CD74 IgA was measured by ELISA in serum samples of axSpA patients, fulfilling the 2009 Assessment of SpondyloArthritis international Society classification criteria. A group of fibromyalgia (FM) and RA patients served as non-inflammatory and inflammatory controls. Newly diagnosed axSpA patients underwent ileocolonoscopy; mucosal biopsies were histopathologically assessed as normal, acute or chronically inflamed. Optimal anti-CD74 IgA cut-off values were determined with a receiver operating characteristics curve. RESULTS: axSpA patients (n = 281) showed higher anti-CD74 IgA levels [mean (s.d.) 18.8 (12.4) U/ml] compared with 100 FM patients [10.9 (5.0) U/ml, P < 0.001] and 34 RA patients [13.7 (9.6) U/ml, P = 0.02]. The area under the receiver operating characteristics curve for diagnosis (axSpA vs FM) was 0.70, providing a sensitivity of 60% and specificity of 87% (cut-off 15 U/ml). Antibody concentrations were not significantly different between axSpA patients with (n = 40) and without (n = 69) gut inflammation (P = 0.83), yielding an area under the receiver operating characteristics curve of 0.51. Anti-CD74 IgA levels were not associated with degree of bone marrow oedema on MRI of the sacroiliac joints, CRP or any other disease-specific feature such as the use of NSAIDs or biological treatment. CONCLUSION: Serum anti-CD74 IgA is a potentially useful diagnostic biomarker for axSpA. However, antibody levels do not correlate with any phenotypical feature, including microscopic gut inflammation, suggesting this to be a disease-specific rather than an inflammatory marker.

Clinical and paraclinical features of small fiber neuropathy in Sjögren's syndrome.

Sjögren's syndrome is a potentially treatable cause of Small Fiber Neuropathy (SFN)-a condition that severely affects patients' quality of life. We therefore aimed to characterize patients with SFN and Sjögren's syndrome to raise awareness of this disease and facilitate its early recognition as an essential step for appropriate treatment. In 97 SFN patients (median age 48 years, 77% female), we studied the clinical features associated with Sjögren's syndrome compared to the idiopathic SFN subtype. According to the current ACR/EULAR classification criteria (Shiboski et al., Ann Rheum Dis 76:9-16, 2017), 24/97 individuals (25%, median age 48.5 years, 75% female) were diagnosed with Sjögren's syndrome. We did not observe any differences in SFN-defining sensory plus symptoms. Furthermore, intraepidermal nerve fiber densities (IENFD) were significantly lower in patients with SFN and Sjögren's syndrome (mean 2.6 ± 1.2/mm) compared to patients with idiopathic SFN (mean 3.2 ± 1.5/mm; p = 0.048). There were no significant group differences when analyzing cerebrospinal fluid (CSF) parameters. We conclude that Sjögren's syndrome-associated SFN is difficult to distinguish from idiopathic forms based on initial clinical symptoms and CSF results. However, lower IENFD values in patients with Sjögren's syndrome-associated SFN might indicate a distinct different pathomechanism in this entity compared to idiopathic SFN.