Anti-synthetase syndrome masquerading as recurrent pneumonia.

Anti-synthetase syndrome (ASS) is a rare inflammatory myopathy with a wide variety of clinical presentations. ASS-related interstitial lung disease (ASS-ILD) presents with rapid onset and progression, which could often be confused with other more common acute processes such as pneumonia, especially when ILD can be the sole manifestation. A woman in her 50s presented with recurrent dyspnoea for 2 months requiring multiple hospital admissions, and each time, she was diagnosed with multifocal pneumonia and treated with antibiotics. On admission, the evaluation revealed a markedly elevated creatine kinase level at 3258 U/L and a CT scan of the chest revealed worsening scattered ground-glass opacities. Given the concern for ILD as the cause of antibiotic failure, she underwent bronchoscopy with bronchoalveolar lavage which revealed non-specific interstitial pneumonia. A subsequent myositis panel revealed a positive anti-Jo-1 antibody, and she was diagnosed with ASS-ILD. She completed a course of intravenous immunoglobulin and methylprednisolone and experienced significant clinical improvement with the resolution of hypoxaemia and improved polyarthralgia.ASS could often be misdiagnosed as other more common acute lung processes, as a clinically subtle course can escape detection given its rarity, as well as its non-specific and highly variable presentations. This case highlights the importance of early suspicion and consideration of performing specific autoantibody testing when evaluating patients with a suspicion of undifferentiated autoimmune condition.

Contemporary Concise Review 2022: Interstitial lung disease.

Novel genetic associations for idiopathic pulmonary fibrosis (IPF) risk have been identified. Common genetic variants associated with IPF are also associated with chronic hypersensitivity pneumonitis. The characterization of underlying mechanisms, such as pathways involved in myofibroblast differentiation, may reveal targets for future treatments. Newly identified circulating biomarkers are associated with disease progression and mortality. Deep learning and machine learning may increase accuracy in the interpretation of CT scans. Novel treatments have shown benefit in phase 2 clinical trials. Hospitalization with COVID-19 is associated with residual lung abnormalities in a substantial number of patients. Inequalities exist in delivering and accessing interstitial lung disease specialist care.

Tofacitinib treatment in anti-glycyl-tRNA synthetase antibody interstitial lung disease - A case report.

Anti-aminoacyl-transfer-RNA synthetase syndrome (ASS) related interstitial lung disease (ILD) is rarely presented initially alongside acute respiratory distress syndrome (ARDS), which in and of itself is a severe condition with a high mortality rate. Additionally, rapidly progressive change is not a common feature in ASS. Numerous case reports have described the efficacy which tofacitinib has on rapidly progressive ILD (RP-ILD). However, none have mentioned the use of tofacitinib in patients with impaired renal function. Herein, a case of ASS involving ILD is reported with the initial presentation of RP-ILD to ARDS being complicated by acute renal failure with an initial complete response to tofacitinib. Patients experiencing unexplained rapidly progressive interstitial pneumonia should be examined thoroughly for the diagnosis of ASS. Furthermore, tofacitinib can also be considered as a choice of treatment even in patients with impaired renal function.

Characteristics and intrasubject variation in the respiratory microbiome in interstitial lung disease.

Recent studies have reported that the lower airway microbiome may play an essential role in the development and progression of interstitial lung disease (ILD). The aim of the current study was to evaluate the characteristics of the respiratory microbiome and intrasubject variation in patients with ILD. Patients with ILD were recruited prospectively for 12 months. The sample size was small (n = 11) owing to delayed recruitment during the COVID-19 pandemic. All subjects were hospitalized and were evaluated by a questionnaire survey, blood sampling, pulmonary function test, and bronchoscopy. Bronchoalveolar lavage fluid (BALF) was obtained at 2 sites, the most and least disease-affected lesions. Sputum collection was also performed. Furthermore, 16S ribosomal RNA gene sequencing was performed using the Illumina platform and indexes of α- and ß-diversity were evaluated. Species diversity and richness tended to be lower in the most-affected lesion than in the least-affected lesion. However, taxonomic abundance patterns were similar in these 2 groups. The phylum Fusobacteria was more prevalent in fibrotic ILD than in nonfibrotic ILD. Inter-sample differences in relative abundances were more prominent in BALF versus sputum specimens. Rothia and Veillonella were more prevalent in the sputum than in BALF. We did not detect site-specific dysbiosis in the ILD lung. BALF was an effective respiratory specimen type for evaluating the lung microbiome in patients with ILD. Further studies are needed to evaluate the causal links between the lung microbiome and the pathogenesis of ILD.

Progressive interstitial lung disease in hypomyopathic dermatomyositis in the COVID-19 pandemic: A case report.

BACKGROUND: Clinically amyopathic dermatomyositis (CADM) is characterized by typical skin lesions with no (amyopathic) or subclinical (hypomyopathic) evidence of muscle involvement. Patients with CADM may also develop rapidly progressive interstitial lung disease (ILD), and have a poor prognosis. However, the diagnosis of rapidly progressive ILD faces a challenge during the severe acute respiratory syndrome coronavirus 2 pandemic. Severe acute respiratory syndrome and ground-glass attenuation on a chest computed tomography scan are the presenting features in both conditions. CASE PRESENTATION: A 45-year-old woman with amyopathic dermatomyositis had acute onset of fever and dyspnea in February 2020. She had abnormal lung findings on CT scan. Polymerase chain reaction testing for SARS-CoV-2 was not available at that time. Chest CT revealed non-specific manifestations that could be either the signs of ILD or SARS-CoV-2 infection. Antiviral therapy was initiated with oseltamivir. Three days later, she had erythema on face, palm, and back. The ratio of lactate dehydrogenase (LDH) isoenzyme 3 to total LDH was elevated. The ratio of LDH isoenzyme 1 to total LDH was declined. Therefore, she was transferred to the rheumatology ward for further treatment. However, she died from respiratory failure 2 weeks later. CONCLUSIONS: We speculate that the altered LDH isoenzyme pattern may be an early biomarker for co-occurrence of CADM and ILD.

Post-COVID Interstitial Lung Disease-The Tip of the Iceberg.

The proportion of symptomatic patients with post-coronavirus 2019 (COVID-19) condition (long COVID) represents a significant burden on the individual as well as on the health care systems. A greater understanding of the natural evolution of symptoms over a longer period and the impacts of interventions will improve our understanding of the long-term impacts of the COVID-19 disease. This review will discuss the emerging evidence for the development of post-COVID interstitial lung disease focusing on the pathophysiological mechanisms, incidence, diagnosis, and impact of this potentially new and emerging respiratory disease.

The Role of Pulmonary Function Testing and Lung Imaging in the Long-Term Follow-Up of Patients with COVID-19 Pneumonia Role of Pulmonary Function Tests and High-Resolution Computed Tomography in Post-COVID-19 Interstitial Lung Disease.

BACKGROUND: Post-COVID-19 Interstitial Lung Disease (PC-ILD) is characterized by fibrotic-like signs at high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) abnormalities after SARS-CoV-2 infection. It is still not clear how frequent these tests should be performed to rule out long-term consequences of COVID-19 pneumonia. OBJECTIVES: The aims of our study were to evaluate the incidence and risk factors of PC-ILD and possibly to propose a long-term follow-up program. METHOD: One-hundred patients, hospitalized in our ward for moderate to critical COVID-19, underwent two follow-up visits at three and 15 months in which PFTs and HRCT were performed. RESULTS: At the 15-month follow-up, 8% of patients showed residual radiological and functional signs consistent with PC-ILD. All but one of these patients had already demonstrated PFTs and HRCT alterations at first follow-up visit, and the last 1 patient showed worsening of lung function during follow-up. These findings highlight the negative predictive value of PFTs at 3-month follow-up for the development of PC-ILD. Aging, severity of COVID-19, and degree of pulmonary involvement during acute infection proved to be significant risk factors for developing PC-ILD. CONCLUSIONS: Our study highlights the importance of PFTs in the long-term follow-up of patients affected by moderate to critical COVID-19 pneumonia. Further studies are needed to confirm our hypothesis that HRCT should be performed only in patients with PFTs abnormalities.

Importance of physician history taking in complementing patient-reported interstitial lung disease questionnaire.

BACKGROUND: Patient-reported interstitial lung disease (ILD) questionnaires are commonly used for the evaluation of ILD patients. However, research to test their performance is scarce. METHODS: This study aimed to assess the performance of the Chest Questionnaire in consecutive ILD patients presenting to a tertiary ILD center. The results of Chest Questionnaires routinely filled by patients were analyzed together with clinical and demographic data retrieved from the patients' medical records. The ability of each questionnaire item to detect positive findings, such as environmental and occupational exposures, was examined relative to any additional findings detected by physician-acquired history. History was obtained by an experienced ILD pulmonologist who had access to the results of the questionnaire during the clinic visit. RESULTS: The final cohort for analysis included 62 patients. Shortness of breath frequency and duration were the questionnaire items with the lowest probability of being filled out by patients. The questionnaire performed well in identifying 96.2% of patients with a positive family history and 90.9% of patients with occupational exposures. However, exposures to mold or birds were frequently missed, self-reported by only 53.1% of exposed patients. Questionnaire's performance was also lower for other exposures associated with ILD (48.3%). An ILD-related exposure was less likely to be identified by the questionnaire in males (p = 0.03), while age had no such effect. CONCLUSIONS: The Chest Questionnaire performed well in several domains, while failing to detect some relevant exposures. Therefore, its use should be accompanied by careful history taking by the physician.

[SARS-CoV-2-Infection and Interstitial Lung Disease: Position paper of the German Respiratory Society]. / SARS-CoV-2-Infektion und interstitielle Lungenerkrankungen ­ Positionspapier der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin.

The SARS-CoV-2 pandemic had a tremendous impact on diagnosis and treatment of interstitial lung diseases (ILD). Especially in the early phase of the pandemic, when the delta variant was prevailling, a huge number of viral pneumonias were observed, which worsened pre-existing, triggered de novo occurence or discovery of previously subclincal interstitial lung diseases. The effect of SARS-CoV-2 infection - without or with accompanying viral pneumonia - on the further development of pre-existing ILD as well of new pulmonary inflitrates and consolidiations is difficult to predict and poses a daily challenge to interdisciplinary ILD boards. This position paper of the German Respiratory Society (DGP e.V.) provides answers to the most pressing questions based on current knowledge.

High-Resolution Computed Tomography of Cystic Lung Disease.

The cystic lung diseases (CLD) are characterized by the presence of multiple, thin-walled, air-filled spaces in the pulmonary parenchyma. Cyst formation may occur with congenital, autoimmune, inflammatory, infectious, or neoplastic processes. Recognition of cyst mimics such as emphysema and bronchiectasis is important to prevent diagnostic confusion and unnecessary evaluation. Chest CT can be diagnostic or may guide the workup based on cyst number, distribution, morphology, and associated lung, and extrapulmonary findings. Diffuse CLD (DCLDs) are often considered those presenting with 10 or more cysts. The more commonly encountered DCLDs include lymphangioleiomyomatosis, pulmonary Langerhans' cell histiocytosis, lymphoid interstitial pneumonia, Birt-Hogg-Dubé syndrome, and amyloidosis/light chain deposition disease.

Post-COVID interstitial lung disease in symptomatic patients after COVID-19 disease.

COVID-19 is often associated with long-lasting pulmonary symptoms. Data are scarce about interstitial lung disease (ILD) in patients following COVID-19 hospitalization with persistent symptoms. We retrospectively reviewed all cases sent to pulmonary post-COVID evaluation due to persistent symptoms between February 2021 and February 2022 (N = 318). All patients with suspected ILD (N = 44) were reviewed at the multidisciplinary discussion. Patient characteristics, symptoms, time since hospitalization, detailed lung function measurements and 6-min walk test (6MWT) were evaluated. The post-COVID ILD suspected group included more men (68.2 vs. 31.8%) with significantly older age compared to the control group (64.0 ± 12.3 vs. 51.3 ± 14.9 years). Most patient needed hospital care for COVID-19 pneumonia (68.6% of all patients and 84.1% of ILD suspected group) and average time since hospitalization was 2.4 ± 2.3 months. Persisting symptoms included fatigue (34%), dyspnoea (25.2%), cough (22.6%), and sleep disorders (insomnia 13.2%; sleepiness 8.2%). Post-COVID ILD presented more often with new symptoms of cough and sleepiness. Functional impairment, especially decreased walking distance and desaturation during 6-min walk test (6MWT) were detected in the ILD-suspected group. Respiratory function test in the post-COVID ILD group showed slight restrictive ventilatory pattern (FVC: 76.7 ± 18.1%, FEV1: 83.5 ± 19.1%, TLC: 85.6 ± 28.1%) and desaturation during 6MWT were detected in 41% of patients. LDCT changes were mainly ground glass opacities (GGO) and/or reticular abnormalities in most cases affecting < 10% of the lungs. Our data indicate that suspected post-COVID ILD is affecting 13.8% of symptomatic patients. High resolution chest CT changes were mainly low extent GGO/reticulation, while long-term lung structural changes need further evaluation.

COVID-19 Pneumonia Followed by Anti-signal Recognition Particle Antibody-positive Fibrosing Interstitial Lung Disease.

Coronavirus disease 2019 (COVID-19) pneumonia is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is frequently accompanied by various sequelae. Interstitial lung diseases (ILDs) are observed in COVID-19 pneumonia patients after recovery, probably due to persistent inflammation in the lungs. We herein report a case of ILD with anti-signal recognition particle antibodies following severe COVID-19 pneumonia. The patient was diagnosed with ILD three months after COVID-19 pneumonia. Although the exact mechanism is unknown, the autoantibody-induced immune response might have been the pulmonary fibrosis trigger in this patient.

A case of antisynthetase syndrome presenting solely with life-threatening interstitial lung disease.

A previously fit and well 38-year-old man presented during the COVID-19 pandemic with dyspnoea, cough and palpitations. C-reactive protein was elevated and chest X-ray demonstrated bilateral lower zone consolidation. SARS CoV-2 swab was negative. He was diagnosed with community-acquired pneumonia and treated with oral antibiotics. He developed severe type 1 respiratory failure and was admitted to the high-dependency unit for non-invasive ventilation. CTPA was negative for pulmonary embolism, instead demonstrating bilateral organising pneumonia. Empirical treatment for swab-negative COVID-19 pneumonitis was started; however, further deterioration ensued and prompted intubation and ventilation. Microbiological testing did not yield any positive results, thereby raising suspicion for the presence of an autoimmune disease. Pulsed intravenous methylprednisolone was administered with good effect. ENA screen was positive for anti-Jo1 and myositis-specific autoantibodies were positive for Ro-52, Ku and PL-12. The patient was extubated and did not exhibit any muscle weakness on clinical examination. Creatine kinase was only mildly elevated. He was diagnosed with amyopathic antisynthetase syndrome - frequently considered as a form of idiopathic inflammatory myopathy (IIM) - and treated with further intravenous methylprednisolone and cyclophosphamide. Oxygen therapy was gradually weaned and the patient discharged on mycophenolate mofetil and a weaning course of oral steroids.

Roles of biomarkers in anti-MDA5-positive dermatomyositis, associated interstitial lung disease, and rapidly progressive interstitial lung disease.

BACKGROUND: Anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis (MDA5+ DM) is significantly associated with interstitial lung disease (ILD), especially rapidly progressive ILD (RPILD) due to poor prognosis, resulting in high mortality rates. However, the pathogenic mechanism of MDA5+ DM-RPILD is unclear. Although some MDA5+ DM patients have a chronic course of ILD, many do not develop RPILD. Therefore, the related biomarkers for the early diagnosis, disease activity monitoring, and prediction of the outcome of RPILD in MDA5+ DM patients should be identified. Blood-based biomarkers are minimally invasive and can be easily detected. METHODS: Recent relative studies related to blood biomarkers in PubMed were reviewed. RESULTS: An increasing number of studies have demonstrated that dysregulated expression of blood biomarkers related to ILD such as ferritin, Krebs von den Lungen-6 (KL-6), surfactant protein-D (SP-D), and cytokines, and some tumor markers in MDA5+ DM may provide information in disease presence, activity, treatment response, and prognosis. These studies have highlighted the great potentials of blood biomarker values for MDA5+ DM-ILD and MDA5+ DM-RPILD. This review provides an overview of recent studies related to blood biomarkers, besides highlighted protein biomarkers, including antibody (anti-MDA5 IgG subclasses and anti-Ro52 antibody), genetic (exosomal microRNAs and neutrophil extracellular traps related to cell-free DNA), and immune cellular biomarkers in MDA5+ DM, MDA5+ DM-ILD, and MDA5+ DM-RPILD patients, hopefully elucidating the pathogenesis of MDA5+ DM-ILD and providing information on the early diagnosis, disease activity monitoring, and prediction of the outcome of the ILD, especially RPILD. CONCLUSIONS: Therefore, this review may provide insight to guide treatment decisions for MDA5+ DM-RPILD patients and improve outcomes.

A review of the challenges, learnings and future directions of home handheld spirometry in interstitial lung disease.

BACKGROUND: Patients with interstitial lung disease (ILD) require regular physician visits and referral to specialist ILD clinics. Difficulties or delays in accessing care can limit opportunities to monitor disease trajectory and response to treatment, and the COVID-19 pandemic has added to these challenges. Therefore, home monitoring technologies, such as home handheld spirometry, have gained increased attention as they may help to improve access to care for patients with ILD. However, while several studies have shown that home handheld spirometry in ILD is acceptable for most patients, data from clinical trials are not sufficiently robust to support its use as a primary endpoint. This review discusses the challenges that were encountered with handheld spirometry across three recent ILD studies, which included home spirometry as a primary endpoint, and highlights where further optimisation and research into home handheld spirometry in ILD is required. Rate of decline in forced vital capacity (FVC) as measured by daily home handheld spirometry versus site spirometry was of primary interest in three recently completed studies: STARLINER (NCT03261037), STARMAP and a Phase II study of pirfenidone in progressive fibrosing unclassifiable ILD (NCT03099187). Unanticipated practical and technical issues led to problems with estimating FVC decline. In all three studies, cross-sectional correlations for home handheld versus site spirometry were strong/moderate at baseline and later timepoints, but longitudinal correlations were weak. Other issues observed with the home handheld spirometry data included: high within-patient variability in home handheld FVC measurements; implausible longitudinal patterns in the home handheld spirometry data that were not reflected in site spirometry; and extreme estimated rates of FVC change. CONCLUSIONS: Home handheld spirometry in ILD requires further optimisation and research to ensure accurate and reliable FVC measurements before it can be used as an endpoint in clinical trials. Refresher training, automated alerts of problems and FVC changes, and patient support could help to overcome some practical issues. Despite the challenges, there is value in incorporating home handheld spirometry into clinical practice, and the COVID-19 pandemic has highlighted the potential for home monitoring technologies to help improve access to care for patients with ILD.

Central and effector memory T cells in peripheral blood of patients with interstitial pneumonia: preliminary clues from a COVID-19 study.

BACKGROUND: SARS-CoV-2 pre-existing T-cell immune reactivity can be present in some people. A general perturbation of the main peripheral lymphocyte subsets has been described in severe COVID-19 patients, but very few studies assessed the general memory T-cell homeostasis in the acute phase of COVID-19. Here, we performed a general analysis of the main memory T cell populations in the peripheral blood of patients admitted to the hospital for a confirmed or probable COVID-19 diagnosis. METHODS: In this cross-sectional study, adult patients (aged ≥ 18 years) needing hospital admission for respiratory disease due to confirmed or probable COVID-19, were recruited before starting the therapeutic protocol for this disease. In addition to the assessment of the general lymphocyte subpopulations in the early phase of COVID-19, central memory T cells (Tmcentr cells: CD45RO+CCR7+) and effector memory T cells (Tmeff cells: CD45RO+CCR7-) were assessed by multi-color flow cytometry, in comparison to a control group. RESULTS: During the study period, 148 study participants were recruited. Among them, 58 patients turned out positive for SARS-CoV-2 PCR (including both patients with interstitial pneumonia [PCR+Pn+] and without this complication [PCR+Pn-]), whereas the remaining 90 patients resulted to be SARS-CoV-2 PCR negative, even though all were affected with interstitial pneumonia [PCR-Pn+]. Additionally, 28 control patients without any ongoing respiratory disease were recruited. A clear unbalance in the T memory compartment emerged from this analysis on the whole pool of T cells (CD3+ cells), showing a significant increase in Tmcentr cells and, conversely, a significant decrease in Tmeff cells in both pneumonia groups (PCR+Pn+ and PCR-Pn+) compared to the controls; PCR+Pn- group showed trends comprised between patients with pneumonia (from one side) and the control group (from the other side). This perturbation inside the memory T cell compartment was also observed in the individual analysis of the four main T cell subpopulations, based upon the differential expression of CD4 and/or CD8 markers. CONCLUSION: Overall, we observed both absolute and relative increases of Tmcentr cells and decrease of Tmeff cells in patients affected with interstitial pneumonia (regardless of the positive or negative results of SARS-CoV-2 PCR), compared to controls. These results need confirmation from additional research, in order to consider this finding as a potential biological marker of interstitial lung involvement in patients affected with viral respiratory infections.

A Delphi consensus statement for the management of post-COVID interstitial lung disease.

INTRODUCTION: As millions of people worldwide recover from COVID-19, a substantial proportion continue to have persistent symptoms, pulmonary function abnormalities, and radiological findings suggestive of post-COVID interstitial lung disease (ILD). To date, there is limited scientific evidence on the management of post-COVID ILD, necessitating a consensus-based approach. AREAS COVERED: A panel of experts in pulmonology and thoracic radiology was constituted. Key questions regarding the management of post-COVID ILD were identified. A search was performed on PubMed and EMBASE and updated till 1 March 2022. The relevant literature regarding the epidemiology, pathophysiology, diagnosis and treatment of post-COVID ILD was summarized. Subsequently, suggestions regarding the management of these patients were framed, and a consensus was obtained using the Delphi approach. Those suggestions which were approved by over 80% of the panelists were accepted. The final document was approved by all panel members. EXPERT OPINION: Dedicated facilities should be established for the care of patients with post-COVID ILD. Symptom screening, pulmonary function testing, and thoracic imaging have a role in the diagnosis. The pharmacologic and non-pharmacologic options for the management of post-COVID ILD are discussed. Further research into the pathophysiology and management of post-COVID ILD will improve our understanding of this condition.

Humoral response among patients with interstitial lung disease vaccinated with the BNT162b2 SARS-Cov-2 vaccine: a prospective cohort study.

BACKGROUND: Patients with interstitial lung disease (ILD) are at high risk of severe COVID-19 infection. Additionally, their anti-inflammatory and antifibrotic treatment may cause immunosuppression. Nevertheless, their ability to mount an adequate immune response to messenger RNA SARS-CoV-2 vaccines was not evaluated. Therefore, we aimed to evaluate the humoral response after the BNT162b2 vaccine among idiopathic pulmonary fibrosis (IPF) patients treated with antifibrotic therapy and among non-IPF ILD patients treated with anti-inflammatory therapy. METHODS: We conducted an observational prospective cohort study to evaluate the level of anti-spike (S-IgG) antibodies after two doses of the BNT162b2 vaccine in patients with ILD. The cohort included 40 patients with idiopathic pulmonary fibrosis (IPF) treated with anti-fibrotic therapy and 29 patients with non-IPF ILD treated with anti-inflammatory therapy. For S-IgG titer measurement, one serology test was drawn from all patients 4-6 months after the second vaccine dose. In addition a control group matched for age and sex was created from a healthy control cohort of 107 patients. The study was conducted in Rabin Medical Center (Israel) between June and August 2021. RESULTS: All patients in the anti-fibrotic arm were seropositive (40/40), corresponding to the matched control group (P = 1.0). The anti-fibrotic arm had a significantly lower median antibody titer in comparison to the matched control group (361.10 [IQR, 207-811] AU/ml vs. 820.75 [IQR, 459-1313] AU/ml; P < 0.001). Only 48.3% (14/29) of patients in the anti-inflammatory arm were seropositive in comparison to 100% (29/29) in the healthy control group (P < 0.001). The anti-inflammatory arm had a significantly lower median antibody titer in comparison to the healthy control group (39.6 [IQR, 4.25-165] AU/ml vs. 970.1 [IQR, 505-1926] AU/ml; P < 0.001). CONCLUSION: IPF patients treated with antifibrotic therapy mount an adequate immune response after 2 doses of the BNT162b2 vaccine, and maintain a 100% seropositivity rate 4-6 months after vaccination. However, their antibody titer was reduced in comparison to a healthy control group. Among patients with non-IPF ILD treated with anti-inflammatory therapy, 48% were seronegative 4-6 months after the second vaccine dose. Moreover, treatment with rituximab caused significant immunosuppression, even in comparison to other anti-inflammatory treatments.