Lung transplantation for interstitial lung disease in idiopathic inflammatory myositis: A cohort study.

In patients with interstitial lung disease (ILD) complicating classical or amyopathic idiopathic inflammatory myopathy (IIM), lung transplantation outcomes might be affected by the disease and treatments. Here, our objective was to assess survival and prognostic factors in lung transplant recipients with IIM-ILD. We retrospectively reviewed data for 64 patients who underwent lung transplantation between 2009 and 2021 at 19 European centers. Patient survival was the primary outcome. At transplantation, the median age was 53 [46-59] years, 35 (55%) patients were male, 31 (48%) had classical IIM, 25 (39%) had rapidly progressive ILD, and 21 (33%) were in a high-priority transplant allocation program. Survival rates after 1, 3, and 5 years were 78%, 73%, and 70%, respectively. During follow-up (median, 33 [7-63] months), 23% of patients developed chronic lung allograft dysfunction. Compared to amyopathic IIM, classical IIM was characterized by longer disease duration, higher-intensity immunosuppression before transplantation, and significantly worse posttransplantation survival. Five (8%) patients had a clinical IIM relapse, with mild manifestations. No patient experienced ILD recurrence in the allograft. Posttransplantation survival in IIM-ILD was similar to that in international all-cause-transplantation registries. The main factor associated with worse survival was a history of muscle involvement (classical IIM). In lung transplant recipients with idiopathic inflammatory myopathy, survival was similar to that in all-cause transplantation and was worse in patients with muscle involvement compared to those with the amyopathic disease.

Efficacy of plasma exchange in patients with anti-MDA5 rapidly progressive interstitial lung disease.

BACKGROUND: Rapidly progressive interstitial lung disease (RP-ILD) is a frequent and severe manifestation of anti-MDA5 dermatomyositis (MDA5-DM) associated with poor outcome. The optimal treatment regimen for MDA5-DM RP-ILD is yet to be determined. Specifically, the value of adding plasma exchange (PLEX) to corticosteroids and immunosuppressants remains unclear. We aimed to evaluate the effect of PLEX on the outcome of patients with MDA5-DM RP-ILD. METHODS: This French nationwide multicentre retrospective study included all MDA5-DM RP-ILD patients from 2012 to 2021 admitted to 18 centres. The primary endpoint was one-year transplant-free survival. RESULTS: 51 patients with MDA5-DM RP-ILD (female 67%; mean age at disease onset: 51 ± 11.6 years) were included. Thirty-two (63%) patients required mechanical ventilation and twenty-five (49%) received PLEX. One-year mortality or lung transplant occurred in 63% cases after a median follow-up of 77 [38-264] days. The Cox proportional hazards multivariable model only retained mechanical ventilation but not PLEX (p = 0.7) as independent predictor of the primary endpoint. One-year transplant-free survival rates in PLEX + vs. PLEX-were 20% vs. 54% (p = 0.01), respectively. The Kaplan-Meier estimated probabilities of one-year transplant-free survival was statistically higher in PLEX-compared to PLEX + patients (p = 0.05). PLEX + compared to PLEX-patients more frequently received mechanical ventilation and immunosuppressants suggesting PLEX + patients had a more severe disease. CONCLUSION: MDA5-DM RP-ILD is associated with poor rate of one-year transplant-free survival. The use of PLEX was not associated with a better outcome albeit they were mainly given to more severe patients. While our study reports the largest series of MDA5-DM RP-ILD given PLEX, these results needs to be interpreted with caution owing the numerous selection, indication and interpretation bias. Further studies are needed to evaluate their efficacy in this setting.

Significance of Sjögren's syndrome and anti-cN1A antibody in myositis patients.

OBJECTIVE: We recently recorded a high prevalence of inclusion body myositis (IBM) in patients with Sjögren's syndrome (SS). Whether myositis patients with SS differ from myositis patients without SS in terms of the characteristics of the myositis is currently unknown. Anti-cytosolic 5'-nucleotidase 1 A (cN1A) has recently been proposed as a biomarker for IBM but is also frequent in SS. Whether anti-cN1A is independently associated with IBM is still an open question. We aimed to assess the significance of SS and anti-cN1A in myositis patients. METHODS: Cumulative data on all myositis patients (EULAR/ACR 2017 criteria) screened for SS (ACR/EULAR 2016 criteria) in a single centre were analysed. Ninety-nine patients were included, covering the whole spectrum of EULAR/ACR 2017 myositis subgroups and with a median follow-up of 6 years (range 1.0-37.5). The 34 myositis patients with SS (myositis/SS+) were compared with the 65 myositis patients without SS (myositis/SS-). RESULTS: . IBM was present in 24% of the myositis/SS+ patients vs 6% of the myositis/SS- group (P = 0.020). None of the IBM patients responded to treatment, whether they had SS or not. Anti-cN1A was more frequent in myositis/SS+ patients (38% vs 6%, P = 0.0005), independently of the higher prevalence of IBM in this group (multivariate P value: 0.02). Anti-cN1A antibody specificity for IBM was 0.96 (95% CI: 0.87, 0.99) in the myositis/SS- group but dropped to 0.70 (95% CI: 0.48, 0.85) in the myositis/SS+ group. INTERPRETATION: In myositis patients, SS is associated with IBM and with anti-cN1A antibodies, independently of the IBM diagnosis. As a consequence, anti-cN1A has limited specificity for IBM in myositis patients with SS.

Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis.

Anti-synthetase syndrome (ASyS)-associated myositis is a major subgroup of the idiopathic inflammatory myopathies (IIM) and is characterized by disease chronicity with musculoskeletal, dermatological and pulmonary manifestations. One of eight autoantibodies against the aminoacyl-transferase RNA synthetases (ARS) is detectable in the serum of affected patients. However, disease-specific therapeutic approaches have not yet been established.To obtain a deeper understanding of the underlying pathogenesis and to identify putative therapeutic targets, we comparatively investigated the most common forms of ASyS associated with anti-PL-7, anti-PL-12 and anti-Jo-1. Our cohort consisted of 80 ASyS patients as well as healthy controls (n = 40), diseased controls (n = 40) and non-diseased controls (n = 20). We detected a reduced extent of necrosis and regeneration in muscle biopsies from PL-12+ patients compared to Jo-1+ patients, while PL-7+ patients had higher capillary dropout in biopsies of skeletal muscle. Aside from these subtle alterations, no significant differences between ASyS subgroups were observed. Interestingly, a tissue-specific subpopulation of CD138+ plasma cells and CXCL12+/CXCL13+CD20+ B cells common to ASyS myositis were identified. These cells were localized in the endomysium associated with alkaline phosphatase+ activated mesenchymal fibroblasts and CD68+MHC-II+CD169+ macrophages. An MHC-I+ and MHC-II+ MxA negative type II interferon-driven milieu of myofiber activation, topographically restricted to the perifascicular area and the adjacent perimysium, as well as perimysial clusters of T follicular helper cells defined an extra-medullary immunological niche for plasma cells and activated B cells. Consistent with this, proteomic analyses of muscle tissues from ASyS patients demonstrated alterations in antigen processing and presentation. In-depth immunological analyses of peripheral blood supported a B-cell/plasma-cell-driven pathology with a shift towards immature B cells, an increase of B-cell-related cytokines and chemokines, and activation of the complement system. We hypothesize that a B-cell-driven pathology with the presence and persistence of a specific subtype of plasma cells in the skeletal muscle is crucially involved in the self-perpetuating chronicity of ASyS myositis. This work provides the conceptual framework for the application of plasma-cell-targeting therapies in ASyS myositis.

Treatment strategies and safety of rechallenge in the setting of immune checkpoint inhibitors-related myositis: a national multicentre study.

OBJECTIVES: The occurrence of immune-related myositis (irM) is increasing, yet there are no therapeutic guidelines. We sought to analyse the current therapeutic strategies of irM and evaluate the outcomes of immune checkpoint inhibitors (ICIs) rechallenge. METHODS: We conducted a nationwide retrospective study between April 2018 and March 2020 including irM without myocardial involvement. Depending on the presence of cutaneous signs or unusual histopathological features, patients were classified into two groups: typical or atypical irM. Therapeutic strategies were analysed in both groups. The modalities and outcomes of ICI rechallenge were reviewed. RESULTS: Among the 20 patients, 16 presented typical irM. Regardless of severity, most typical irM were treated with steroid monotherapy (n = 14/16) and all had a complete response within ≤3 weeks. The efficacy of oral steroids for non-severe typical irM (n = 10) was the same with low-dose (≤0.5 mg/kg/day) or high-dose (1 mg/kg/day). Severe typical irM were successfully treated with intravenous methylprednisolone. Atypical irM (n = 4) had a less favourable evolution, including one irM-related death, and required heavy immunosuppression. ICIs were safely reintroduced in nine patients presenting a moderate (n = 6) or a severe (n = 3) irM. CONCLUSION: Our data highlight that steroid monotherapy is an effective treatment for typical irM, either with prednisone or with intravenous methylprednisone pulses depending on the severity. The identification of unusual features is important in determining the initial therapeutic strategy. The outcomes of rechallenged patients are in favour of a safe reintroduction of ICI following symptom resolution and creatin kinase (CK) normalization in moderate and severe forms of irM.

High prevalence of myeloid neoplasms in adults with non-Langerhans cell histiocytosis.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis that most commonly affects adults and is driven by a high frequency of mutations in BRAF, MAP2K1, and kinases promoting MAPK signaling. Because of the relative rarity of ECD, key clinical features of the disease may not be well defined. Across a multi-institutional cohort of 189 patients with ECD and ECD overlapping with Langerhans cell histiocytosis (so-called mixed histiocytosis [MH]), we identified an unexpected and heretofore undescribed frequent occurrence of myeloid neoplasms among patients with ECD and MH. Some 10.1% (19/189) of patients with ECD have an overlapping myeloid neoplasm, most commonly occurring as a myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), or mixed MDS/MPN overlap syndrome (including chronic myelomonocytic leukemia). Consistent with this, molecular analysis frequently detected hallmark driver mutations of myeloid neoplasms (such as JAK2V617F and CALR mutations) coexisting with those characteristic of histiocytosis (such as BRAFV600E and MAP2K1 mutations). Histiocytosis patients diagnosed with a concomitant myeloid malignancy were significantly older at diagnosis and more commonly presented with MH than those without a myeloid malignancy. In some cases, the presence of distinct kinase mutations in the histiocytosis and myeloid neoplasm resulted in discordant and adverse responses to kinase-directed targeted therapies. These data highlight the clinical importance of evaluating adults with histiocytosis for a concomitant myeloid neoplasm.

Immunopathogenesis of the Anti-Synthetase Syndrome.

Among the inflammatory myopathies, anti-tRNA-synthetase syndrome (ASyS) is a severe autoimmune condition characterized by extramuscular involvement, affecting especially the lungs. ASyS specific serological markers are anti-tRNA-synthetase autoantibodies, among which anti-histidyl-tRNA-synthetase is the most common. In the past decades, ASyS has been distinguished by unique histological features attributed to a specific pathogenesis. Research has highlighted the role of environmental factors and infections as possible triggers. Tissue modifications of histidyl-tRNA-synthetase (HisRS) expression might be responsible for the recruitment and activation of both innate and adaptive immune cells. HisRS not only acts through antigenic properties, but also through many others, including chemoattraction, innate pathway activation, and cytokine-like functions. Favored by a certain genetic background, this whole activation of immunity results in widespread and specific tissue damage and finally leads to visible heterogeneous symptoms characterizing the disease state. Understanding the pathogenesis of ASyS is essential to improving patient care by identifying biomarkers and designing new therapeutic strategies accordingly. Therefore, this review details the recent hypotheses concerning the dynamic of ASyS pathogenesis with the aim of enlightening the development of new therapeutic axes in the future.

Antisynthetase syndrome pathogenesis: knowledge and uncertainties.

PURPOSE OF REVIEW: Antisynthetase syndrome (ASyS) is an acquired myopathy characterized by the presence of myositis-specific autoantibodies directed against tRNA-synthetases. ASyS is potentially life threatening due to lung involvement and treatment remains a challenge to date. With symptoms not limited to muscles but also involving lung, skin and joints, ASyS appears specific and has a particular pathogenesis, different from the other inflammatory myopathies. This review is intended to discuss the current understanding of ASyS pathogenesis, pointing its current knowledge and also the crucial prospects that may lead to critical improvement of ASyS care. RECENT FINDINGS: Regarding ASyS pathogenesis, initiation of the disease seems to arise in a multifactorial context, with first lesions occurring within the lungs. This may lead to aberrant self-antigen exposure and tolerance breakdown. The consequences are abnormal activation of both innate and adaptive immunity, resulting in the patients with favourable genetic background to autoimmune-mediated organ lesions. Immune and nonimmune roles of the antigen, as well as antigen presentation leading to specific T-cell and B-cell activation and to the production of specific autoantibodies belong to the disease process. SUMMARY: This work aims to detail ASyS pathogenesis understanding, from initiation to the disease propagation and target tissue lesions, in order to considering future treatment directions.

Involvement of NK Cells and NKp30 Pathway in Antisynthetase Syndrome.

Antisynthetase syndrome (aSS) is characterized by the association of interstitial lung disease and myositis with anti-tRNA synthetase autoantibodies. Immune mechanisms leading to aSS could be initiated in the lungs, but the role of NK cells has not yet been studied. Both extensive NK cell phenotype and functions were compared between 33 patients and 26 controls. Direct and redirected polyfunctionality assays (degranulation and intracellular production of TNF-α and IFN-γ) were performed spontaneously or after IL-12 plus IL-18 stimulation in the presence of K562 or P815 target cells, respectively. NK cells from inactive patients showed normal phenotype, whereas active aSS revealed a differentiated NK cell profile, as indicated by increased CD57 and Ig-like transcript 2 and an inability to produce IFN-γ (p = 0.002) compared with controls. Importantly, active aSS was more specifically associated with a significant NKp30 decrease (p = 0.009), although levels of mRNA and intracellular protein were similar in aSS and healthy controls. This NKp30 decrease was strongly correlated with reduced NK cell polyfunctionality in both direct and redirected killing assays with anti-NKp30 Abs (p = 0.009 and p = 0.03, respectively), confirming its important impact in aSS. Histological studies revealed massive infiltrations of NK cells inside the lungs of aSS patients (148 versus 11/mm(2)). Taken together, these data suggest that NK cells and NKp30 could play a role in aSS pathogenesis.

Dermatomyositis With or Without Anti-Melanoma Differentiation-Associated Gene 5 Antibodies: Common Interferon Signature but Distinct NOS2 Expression.

The anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody is specifically associated with dermatomyositis (DM). Nevertheless, anti-MDA5(+)-patients experience characteristic symptoms distinct from classic DM, including severe signs of extramuscular involvement; however, the clinical signs of myopathy are mild or even absent. The morphological and immunological features are not yet described in adulthood. Data concerning the pathophysiology of anti-MDA5 DM are sparse; however, the importance of the interferon (IFN) type I pathway involved in DM has been shown. Our aim was to define morphological alterations of the skeletal muscle and the intrinsic immune response of anti-MDA5-positive DM patients. Immunohistological and RT-PCR analysis of muscle biopsy specimens from anti-MDA5 and classic DM were compared. Those with anti-MDA5 DM did not present the classic features of perifascicular fiber atrophy and major histocompatibility complex class I expression. They did not show significant signs of capillary loss; tubuloreticular formations were observed less frequently. Inflammation was focal, clustering around single vessels but significantly less intense. Expression of IFN-stimulated genes was up-regulated in anti-MDA5 DM; however, the IFN score was significantly lower. Characteristic features were observed in anti-MDA5 DM and not in classic DM patients. Only anti-MDA5 DM showed numerous nitric oxide synthase 2-positive muscle fibers with sarcoplasmic colocalization of markers of regeneration and cell stress. Anti-MDA5-positive patients demonstrate a morphological pattern distinct from classic DM.

High risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody.

Cancer can occur in patients with inflammatory myopathies. This association is mainly observed in dermatomyositis, and myositis-specific antibodies have allowed us to delineate patients at an increased risk. Malignancy is also reported in patients with necrotizing autoimmune myopathies, but the risk remains elusive. Anti-signal recognition particle or anti-HMGCR antibodies have been specifically associated with necrotizing autoimmune myopathies. We aimed at screening the incidence of cancer in necrotizing autoimmune myopathies. A group of patients (n = 115) with necrotizing autoimmune myopathies with or without myositis-specific antibodies was analysed. Malignancy occurred more frequently in seronegative necrotizing autoimmune myopathies patients and in HMGCR-positive patients compared to anti-signal recognition particle positive patients. Synchronous malignancy was diagnosed in 21.4% and 11.5% of cases, respectively, and incidence of cancer was higher compared to the general population in both groups. No specific type of cancer was predominant. Patients suffering from a synchronous cancer had a decreased median survival time. Cancer screening is necessary in seronegative necrotizing autoimmune myopathies and in HMGCR-positive patients but not in anti-signal recognition particle-positive patients.

Association of both Langerhans cell histiocytosis and Erdheim-Chester disease linked to the BRAFV600E mutation.

Histiocytoses are a group of heterogeneous diseases that mostly comprise Langerhans cell histiocytosis (LCH) and non-LCH. The association of LCH with non-LCH is exceptional. We report 23 patients with biopsy-proven LCH associated with Erdheim-Chester disease (ECD) (mixed histiocytosis) and discuss the significance of this association. We compare the clinical phenotypes of these patients with those of 56 patients with isolated LCH and 53 patients with isolated ECD. The average age at diagnosis was 43 years. ECD followed (n = 12) or was diagnosed simultaneously with (n = 11) but never preceded LCH. Although heterogeneous, the phenotype of patients with mixed histiocytosis was closer to that of isolated ECD than to that of isolated LCH (principal component analysis). LCH and ECD improved in response to interferon alpha-2a treatment in only 50% of patients (8 of 16). We found the BRAF(V600E) mutation in 11 (69%) of 16 LCH lesions and in 9 (82%) of 11 ECD lesions. Eight patients had mutations in both ECD and LCH biopsies. Our findings indicate that the association of LCH and ECD is not fortuitous and suggest a link between these diseases involving the BRAF(V600E) mutation.

Anti-Jo-1 antibody-positive patients show a characteristic necrotizing perifascicular myositis.

Idiopathic inflammatory myopathies can be classified as polymyositis, dermatomyositis, immune-mediated necrotizing myopathy, sporadic inclusion body myositis or non-specific myositis. Anti-Jo-1 antibody-positive patients are assigned to either polymyositis or dermatomyositis suggesting overlapping pathological features. We aimed to determine if anti-Jo-1 antibody-positive myopathy has a specific morphological phenotype. In a series of 53 muscle biopsies of anti-Jo-1 antibody-positive patients, relevant descriptive criteria defining a characteristic morphological pattern were identified. They were tested in a second series of anti-Jo-1 antibody-positive patients and compared to 63 biopsies from patients suffering from other idiopathic inflammatory myopathies. In anti-Jo-1 antibody-positive patients, necrotic fibres, which strongly clustered in perifascicular regions, were frequently observed. Sarcolemmal complement deposition was detected specifically in perifascicular areas. Inflammation was mainly located in the perimysium and around vessels in 90.6%. Perimysial fragmentation was observed in 90% of cases. Major histocompatibility complex class I staining was diffusely positive, with a perifascicular reinforcement. Multivariate analysis showed that criteria defining perifascicular pathology: perifascicular necrosis, atrophy, and perimysial fragmentation allow the distinction of anti-Jo-1 antibody-positive patients, among patients suffering from other idiopathic inflammatory myopathies. Anti-Jo-1 antibody-positive patients displayed perifascicular necrosis, whereas dermatomyositis patients exhibited perifascicular atrophy.

Seronegative polyarthritis revealing antisynthetase syndrome: a multicentre study of 40 patients.

OBJECTIVE: The aim of this study was to determine the frequency and characteristics of antisynthetase syndrome (ASS) revealed by polyarthritis. METHODS: First we conducted a retrospective single-centre study to assess the frequency of ASS patients who presented with polyarthritis without pulmonary and/or muscle symptoms. Secondly, we conducted a larger, multicentre study in order to describe the clinical characteristics of these patients. Exclusion criteria were the presence of RF, the presence of ACPA and overlap with another CTD. RESULTS: In the single-centre study, polyarthritis was the first manifestation in 12 of 45 ASS patients (27%). An additional 28 patients were collected for the multicentre study, resulting in a total population of 40 ASS patients who presented with polyarthritis. The mean delay from polyarthritis onset to ASS diagnosis was 27 months (s.d. 40). Pulmonary and muscle symptoms were uncommon at ASS diagnosis (40% and 32.5%, respectively) and were dramatically delayed [mean delay after polyarthritis onset of 41 months (s.d. 53) and 21 months (s.d. 14), respectively]. Mechanic's hands and cutaneous signs of DM occurred in 25% and 22.5%, respectively, with a mean delay of 10 months (s.d. 10) and 31 months (s.d. 21), respectively. When present (32%), RP was the earliest non-articular manifestation [mean delay 3 months (s.d. 23) after polyarthritis onset]. On HEp-2 cells, antinuclear and/or cytoplasmic fluorescence was found in 70% of cases, with specificity for various anti-aminoacyl tRNA synthetase (anti-ARS) antibodies. CONCLUSION: ASS may be revealed by polyarthritis. To decrease the delay in diagnosis of ASS, pulmonary and muscle symptoms and anti-ARS antibodies might usefully be searched for in seronegative polyarthritis patients, especially in those with RP.

Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation.

Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAFV600E gain-of-function mutations have been observed in 57% of cases of Langerhans cell histiocytosis (LCH) and 54% of cases of Erdheim-Chester disease (ECD), but not in other types of histiocytoses. Targeted therapy with an inhibitor of mutated BRAF (vemurafenib) improves survival of patients with melanoma. Here, we report vemurafenib treatment of 3 patients with multisystemic and refractory ECD carrying the BRAFV600E mutation; 2 also had skin or lymph node LCH involvement. The patients were assessed clinically, biologically (CRP values), histologically (skin biopsy), and morphologically (positron emission tomography [PET], computed tomography and magnetic resonance imaging). For all patients, vemurafenib treatment led to substantial and rapid clinical and biologic improvement, and the tumor response was confirmed by PET, computed tomography, and/or magnetic resonance imaging 1 month after treatment initiation. For the first patient treated, the PET response increased between months 1 and 4 of treatment. The treatment remained effective after 4 months of follow-up although persistent disease activity was still observed. Treatment with vemurafenib, a newly approved BRAF inhibitor, should be considered for patients with severe and refractory BRAFV600E histiocytoses, particularly when the disease is life-threatening.

Long-term outcome of infliximab in severe chronic and refractory systemic sarcoidosis: a report of 16 cases.

OBJECTIVES: Infliximab (IFX) appears to be effective in refractory sarcoidosis. However, data are lacking regarding its efficacy in severe sarcoidosis (i.e. with cardiac and/or neurological involvement). METHODS: Retrospective single-centre study including 16 unselected consecutive patients with biopsy proven, severe, and resistant sarcoidosis, who were treated by infliximab (3 or 5 mg /kg at 0, 2 and 6 weeks, then every 8 weeks) between 2005 and 2013. RESULTS: Following IFX therapy we observed an improvement in 92% of cases, with a marked decrease of the severity score [median score 6 (3-12) vs. 2 (1-8), p<0.0001] and trend toward steroid sparing effect [12.5 (0-40) vs. 8.5 mg/d (0-30), p=0.11] between baseline and the end of follow-up, respectively. Regarding the index organ response, we observed a remission of cardiac and central nervous system involvements in 4 out of 4 and 11 out 12 cases, respectively. Thirty-eight percent of patients experienced a relapse. After a median follow-up of 57 months (2 to 91), we observed 7 (44%) infectious complications, 1 paradoxical cutaneous granuloma and 1 leucoencephalopathy. Infectious complications were mostly observed in male [6/7 (86%), p=0.06], with a longer duration of steroids (108 vs. 39 months, p=0.11) and immunosuppressant use prior IFX (42 vs. 24 months, p=0.08) compared to their negative counterpart, respectively. CONCLUSIONS: IFX was efficient in severe and refractory sarcoidosis. Infectious complications were frequent and occurred mainly in male patients with longer duration of steroids and immunosuppressant use prior to IFX.