High risk of lung cancer in surfactant-related gene variant carriers.

BACKGROUND: Several rare surfactant-related gene (SRG) variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing. We aimed to study the epidemiology and phenotype of lung cancer in an international cohort of SRG variant carriers. METHODS: We conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomere-related gene (TRG) variant carriers. RESULTS: We identified 99 SRG adult variant carriers (SFTPA1 (n=18), SFTPA2 (n=31), SFTPC (n=24), ABCA3 (n=14) and NKX2-1 (n=12)), including 20 (20.2%) with lung cancer (SFTPA1 (n=7), SFTPA2 (n=8), SFTPC (n=3), NKX2-1 (n=2) and ABCA3 (n=0)). Among SRG variant carriers, the odds of lung cancer was associated with age (OR 1.04, 95% CI 1.01-1.08), smoking (OR 20.7, 95% CI 6.60-76.2) and SFTPA1/SFTPA2 variants (OR 3.97, 95% CI 1.39-13.2). Adenocarcinoma was the only histological type reported, with programmed death ligand-1 expression ≥1% in tumour cells in three samples. Cancer staging was localised (I/II) in eight (40%) individuals, locally advanced (III) in two (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and three received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patients versus TRG patients was 18.1 (95% CI 7.1-44.7). CONCLUSIONS: The high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular computed tomography scan follow-up should be evaluated.

Prognostic impact of venous thromboembolism on the course of sarcoidosis: A multicenter retrospective case-control study.

Sarcoidosis is an independent risk factor for venous thromboembolism (VTE). However, the characteristics and clinical evolution of sarcoidosis patients presenting a VTE (sarcoidosis/VTE group) in the course of their disease are not known. Consequently, if VTE occurrence is associated with a more severe disease is still pending. We conducted a retrospective case-control study of sarcoidosis/VTE patients compared to matched sarcoidosis controls without VTE in two French tertiary centers, analysed and compared the clinical, biological, functional, imaging and evolutive profiles of the two groups. Sixty-one patients were included with at least one episode of VTE during course of sarcoidosis. At sarcoidosis onset (before/at the time of VTE occurrence) the number of affected organs, radiological stages and pulmonary functional tests were not significantly different between the two groups. In contrast, we found that sarcoidosis/VTE patients required more frequently a systemic immunosuppressive therapy (corticosteroids and/or immunosuppressors, 79% versus 58%; p = 0.008). The functional course was also poorer in sarcoidosis/VTE patients with a more frequent decrease in functional vital capacity (33% versus 18% in sarcoidosis/VTE patients and controls, respectively, p = 0.008). Finally, sarcoidosis/VTE patients presented more frequently with pulmonary hypertension (10% versus 1% in patients and controls, respectively, p = 0.006), and their survival was significantly worse (log-rank p <0.001). The occurrence of VTE during sarcoidosis is associated with a more severe disease and a poorer prognosis. The occurrence of VTE during sarcoidosis might signal a more inflammatory and/or evolutive disease in sarcoidosis/VTE patients and should be taken in consideration when designing therapeutic strategies for them.

How to Tackle the Diagnosis and Treatment in the Diverse Scenarios of Extrapulmonary Sarcoidosis.

Extrapulmonary sarcoidosis occurs in 30-50% of cases of sarcoidosis, most often in association with pulmonary involvement, and virtually any organ can be involved. Its incidence depends according to the organs considered, clinical phenotype, and history of sarcoidosis, but also on epidemiological factors like age, sex, geographic ancestry, and socio-professional factors. The presentation, symptomatology, organ dysfunction, severity, and lethal risk vary from and to patient even at the level of the same organ. The presentation may be specific or not, and its occurrence is at variable times in the history of sarcoidosis from initial to delayed. There are schematically two types of presentation, one when pulmonary sarcoidosis is first discovered, the problem is then to detect extrapulmonary localizations and to assess their link with sarcoidosis, while the other presentation is when extrapulmonary manifestations are indicative of the disease with the need to promptly make the diagnosis of sarcoidosis. To improve diagnosis accuracy, extrapulmonary manifestations need to be known and a medical strategy is warranted to avoid both under- and over-diagnosis. An accurate estimation of impairment and risk linked to extrapulmonary sarcoidosis is essential to offer the best treatment. Most frequent extrapulmonary localizations are skin lesions, arthritis, uveitis, peripheral lymphadenopathy, and hepatic involvement. Potentially severe involvement may stem from the heart, nervous system, kidney, eye and larynx. There is a lack of randomized trials to support recommendations which are often derived from what is known for lung sarcoidosis and from the natural history of the disease at the level of the respective organ. The treatment needs to be holistic and personalized, taking into account not only extrapulmonary localizations but also lung involvement, parasarcoidosis syndrome if any, symptoms, quality of life, medical history, drugs contra-indications, and potential adverse events and patient preferences. The treatment is based on the use of anti-sarcoidosis drugs, on treatments related to organ dysfunction and supportive treatments. Multidisciplinary discussions and referral to sarcoidosis centers of excellence may be helpful for difficult diagnosis and treatment decisions.

Sarcoidosis-Like Cancer-Associated Granulomatosis: Characteristics and a Case-Control Comparison with Sarcoidosis.

(1) Background: Systemic granulomatosis developed in a context of malignancy has already been reported. Our objective was to describe the clinical, radiological, functional, biological, and evolutive characteristics of sarcoidosis-like cancer-associated granulomatosis (SLCAG) and to compare them to those of sarcoidosis. (2) Methods: 38 patients with a biopsy-proven SLCAG developed after a diagnostic of malignancy were included. The control group consisted of sarcoidosis patients matched for age, sex, and radiologic stage. Clinical, biological, physiological, radiological, and outcome data were collected. (3) Results: The mean age of SLCAG patients was 51 ± 14 years. They were diagnosed within 15 ± 14 months of the cancer diagnosis (breast cancer most frequently). All SLCAG patients presented a thoracic involvement, extrathoracic locations were observed in 32% of subjects. SLCAG was more often asymptomatic than sarcoidosis (p < 0.0001). During follow-up, systemic treatment was less often required in SLCAG than in sarcoidosis (58% vs. 32%, p = 0.04 respectively) and SLCAG were characterized by a significantly less severe progression profile according to the Sarcoid Clinical Activity Classification, with a complete recovery more frequent at 5 years (p = 0.03). (4) Conclusion: This case-control study shows that SLCAG differs from sarcoidosis with a significantly more benign course. These results might argue for true differences in the physiopathology, which remain to be elucidated.

Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer.

INTRODUCTION: Interstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex SP-A. Only 11 SFTPA1 or SFTPA2 mutations have so far been reported worldwide, of which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives. METHODS: The consequences of the 11 SFTPA1 or SFTPA2 mutations were analysed both in vitro, by studying the production and secretion of the corresponding mutated proteins and ex vivo, by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented. RESULTS: For the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6-65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic. DISCUSSION: This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic SFTPA1 or SFTPA2 mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.

Predictors of mortality in fibrosing pulmonary sarcoidosis.

INTRODUCTION: Pulmonary fibrosing sarcoidosis is associated with increased mortality. This study was aimed to explore the prognosis value of a panel of parameters for predicting mortality. METHODS: This retrospective study included 216 patients with confirmed stage 4 pulmonary sarcoidosis. Stage 4 diagnosis date served as baseline. The following information was systematically present at baseline: epidemiological characteristics; treatments; pulmonary function; composite physiologic index (CPI); systolic pulmonary artery pressure at echocardiography; pulmonary fibrosis extent, main pulmonary artery/ascending aorta diameters ratio (MPAD/AAD) and MPAD/body surface area (BSA) measured and calculated using computed tomography, Walsh's algorithm based on CPI, lung fibrosis extent and MPAD/AAD ratio, and modified Walsh's algorithm with MPAD/BSA replacing MPAD/AAD allowed to estimate good or bad prognosis profiles. The primary outcome of the study was all cause mortality and lung transplantation. The value of baseline parameters was tested as predictors of mortality using univariate and multivariate analyses. RESULTS: Median follow-up was 105 months. There were 41 deaths and 5 transplantations. At multivariate analysis, survival was independently predicted by several parameters including CPI, lung fibrosis extent, pulmonary hypertension at echography or MPAD/BSA ratio, Walsh's algorithm, and geographic origin. The modified Walsh's algorithm was most highly predictive. CONCLUSION: Survival was best predicted by geographic origin, lung fibrosis extent, PH at echography or MPAD/BSA ratio, as well as by various scores among them the modified Walsh's algorithm had very high predictive value thanks to MPAD/BSA ratio which accurately predicted mortality.

Pilot experience of multidisciplinary team discussion dedicated to inherited pulmonary fibrosis.

BACKGROUND: Genetic testing is proposed for suspected cases of monogenic pulmonary fibrosis, but clinicians and patients need specific information and recommendation about the related diagnosis and management issues. Because multidisciplinary discussion (MDD) has been shown to improve accuracy of interstitial lung disease (ILD) diagnosis, we evaluated the feasibility of a genetic MDD (geneMDD) dedicated to the indication for and interpretation of genetic testing. The geneMDD group met monthly and included pediatric and adult lung specialists with ILD expertise, molecular and clinical geneticists, and one radiologist. Hematologists, rheumatologists, dermatologists, hepatologists, and pathologists were also invited to attend. RESULTS: Since 2016, physicians from 34 different centers in 7 countries have participated in the geneMDD. The medical files of 95 patients (53 males) have been discussed. The median age of patients was 43 years [range 0-77], 10 were ≤ 15 years old, and 6 were deceased at the time of the discussion. Among 85 analyses available, the geneMDD considered the rare gene variants pathogenic for 61: 37 variants in telomere-related genes, 23 variants in surfactant-related genes and 1 variant in MARS. Genetic counseling was offered for relatives of these patients. The geneMDD therapeutic proposals were as follows: antifibrotic drugs (n = 25), steroids or immunomodulatory therapy (n = 18), organ transplantation (n = 21), watch and wait (n = 21), or best supportive care (n = 4). CONCLUSION: Our experience shows that a dedicated geneMDD is feasible regardless of a patient's age and provides a unique opportunity to adapt patient management and therapy in this very rare condition.

Indications for treatment of sarcoidosis.

PURPOSE OF REVIEW: To describe the current knowledge on indications for sarcoidosis treatment. RECENT FINDINGS: Despite the lack of evidence-based recommendations, the sarcoidosis community has adopted the concept of starting systemic anti-inflammatory treatment because of potential danger (risk of severe dysfunction on major organs or death) or unacceptable impaired quality of life (QoL). On the contrary, while QoL and functionality are patients' priorities, few studies have evaluated treatment effect on patient-reported outcomes. The awareness of long-term corticosteroids toxicities and consequences on QoL and the emergence of novel drugs have changed therapeutic management. Second-line therapy, mainly methotrexate and azathioprine, are indicated for corticosteroids sparing or corticosteroids-resistant sarcoidosis. TNF-α inhibitors are a useful third-line therapy in chronic refractory disease. In addition to organ-targeted treatment, efforts should also be taken for treating nonorgan-specific symptoms, such as physical training for fatigue, and various disease complications. SUMMARY: Clinicians should offer a tailored treatment for each patient and ensure a holistic multidisciplinary approach, including pharmacological and nonpharmacological interventions. Patient-centered communication is critical to drive shared decisions, in particular for the tricky situation of isolated impaired QoL as the unique therapeutic indication. Once treatment is decided, clinicians should define a clear therapeutic plan, including goals and instruments to assess response.

High prevalence of spondyloarthritis in sarcoidosis patients with chronic back pain.

INTRODUCTION: Chronic back pain (CBP) is a frequent complaint in patients with sarcoidosis, which challenges the clinician as multiples causes may potentially underlie this symptom. Interestingly, some reports suggest that the coexistence of sarcoidosis and spondyloarthritis (SpA) may be frequent. This study aimed to determine the prevalence of axial radiographic and non-radiographic SpA in patients with sarcoidosis and CBP and assess the association between patient characteristics and SpA. METHODS: This cross-sectional study enrolled 64 patients with a diagnosis of sarcoidosis and CBP. Patients describing CBP underwent a full spine MRI and radiography. All patients with inflammatory CBP underwent complementary sacroiliac joint MRI. The diagnosis of axial SpA was based on the Assessment of SpondyloArthritis International Society classification criteria. RESULTS: Among the 64 patients (49 women) with sarcoidosis and CBP, 29 had inflammatory pain; 15/64 had a diagnosis of SpA (23.4% [95% CI: 13.7-35.6], 14/29 (48.3% [95% CI: 29.5-67.5] of those with inflammatory back pain). MRI sacroiliitis was found in 13 patients. On both univariate and multivariate analysis, SpA diagnosis was associated with inflammatory CBP (OR=28.5, 95% CI: 1.91-425.4) and sarcoidosis limited to the thorax (OR=6.74, 95% CI: 1.08-42.1). SpA was associated with young age (p = 0.0093) and male sex (p = 0.021) only on univariate analysis. Besides, 12/64 patients (18.8%, 95% CI: 10.1-30.5) had a diagnosis of sarcoidosis spine bone lesions, 7/64 (10.9%, 95% CI: 4.5-21.2) symptomatic vertebral fracture and 30/64 (46.9%, 95% CI: 34.3-59.8) degenerative spine. CONCLUSIONS: The prevalence of SpA is increased in sarcoidosis patients with inflammatory back pain. The systematic use of spine and sacroiliac MRI in this subgroup is justified. The association between other patient features and SpA needs further confirmation.

Regulator of telomere length 1 (RTEL1) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes.

Regulator of telomere length 1 (RTEL1) mutations have been evidenced in 5-9% of familial pulmonary fibrosis; however, the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly understood.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lungs of controls, as well as in RTEL1 and telomerase reverse transcriptase (TERT) mutation carriers.We identified 35 subjects from 17 families. Median age at diagnosis of ILD was 53.1 years (range 28.0-80.6). The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%), secondary ILD (n=7, 20%) and unclassifiable fibrosis or interstitial pneumonia with autoimmune features (n=7, 20%). The median transplant-free and overall survival periods were 39.2 months and 45.3 months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free survival. Extra-pulmonary manifestations were less frequent as compared to other telomere-related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations (including this series) and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non-idiopathic diseases and the low prevalence of extra-pulmonary manifestations.Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, as well as by alveolar macrophages and lymphocytes, but not by fibroblasts.

G908R NOD2 variant in a family with sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic disease characterized by the formation of immune granulomas in various organs, mainly the lungs and the lymphatic system. Exaggerated granulomatous reaction might be triggered in response to unidentified antigens in individuals with genetic susceptibility. The present study aimed to determine the genetic variants implicated in a familial case of sarcoidosis. METHODS: Sarcoidosis presentation and history, NOD2 profile, NF-κB and cytokine production in blood monocytes/macrophages were evaluated in individuals from a family with late appearance of sarcoidosis. RESULTS: In the present study, we report a case of familial sarcoidosis with typical thoracic sarcoidosis and carrying the NOD2 2722G > C variant. This variant is associated with the presence of three additional SNPs for the IL17RA, KALRN and EPHA2 genes, which discriminate patients expressing the disease from others. Despite a decrease in NF-κB activity, IL-8 and TNF-A mRNA levels were increased at baseline and in stimulated conditions. CONCLUSIONS: Combination of polymorphisms in the NOD2, IL17RA, EPHA2 and KALRN genes could play a significant role in the development of sarcoidosis by maintaining a chronic pro-inflammatory status in macrophages.

Outcome of patients with sarcoidosis refractory to TNF antagonists: a case series.

Background: Tumor necrosis factor (TNF) antagonists have been reported as an efficient third-line therapy for sarcoidosis but there is no data regarding patients who do not respond to this treatment. Objective: To report the characteristics, the outcome and the response to therapy of patients with sarcoidosis resistant to TNF antagonists. Methods: Patients from the French STAT (Sarcoidosis Treatment with Anti-TNF) registry who were classified as non-responders and who were followed-up for >1 year were included. The response to further therapies was classified as complete response, or partial response, and the others were classified as non-responders. Results: Among the 132 patients from the registry, 14 were considered as non-responders to anti-TNF. Nine patients (66% of women; mean age 48 years) were analyzed. The mean number of organs involved was 4.2. Seven patients were previously treated with more than 2 immunosuppressive treatments. The mean duration of the anti-TNF treatment was 9 months (range, 3-24). After a mean follow-up duration of 58 months (median, 35; range, 19-128) a complete response was observed in 2/9 cases, a partial response in 5/9 cases, and 2/9 cases were considered as non-responders. In all but one patient, the immunosuppressant that allowed the clinical response had previously been used. Furthermore, the dosage was not necessarily increased to gain efficacy. Non-responders were treated by corticosteroids only because of their comorbidities or noncompliance. Conclusion: In patients who do not respond to TNF antagonists, previously used immunosuppressants may be useful. Excluding a differential diagnosis, assessing compliance and testing for anti-drug antibodies should be systematic. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 371-375).

The Lung in Dysregulated States of Humoral Immunity.

In common variable immunodeficiency, lung manifestations are related to different mechanisms: recurrent pneumonias due to encapsulated bacteria responsible for diffuse bronchiectasis, diffuse infiltrative pneumonia with various patterns, and lymphomas, mostly B cell extranodal non-Hodgkin type. The diagnosis relies on significant serum Ig deficiency and the exclusion of any primary or secondary cause. Histopathology may be needed. Immunoglobulin (IgG) replacement is crucial to prevent infections and bronchiectasis. IgG4-related respiratory disease, often associated with extrapulmonary localizations, presents with solitary nodules or masses, diffuse interstitial lung diseases, bronchiolitis, lymphadenopathy, and pleural or pericardial involvement. Diagnosis relies on international criteria including serum IgG4 dosage and significantly increased IgG4/IgG plasma cells ratio in pathologically suggestive biopsy. Respiratory amyloidosis presents with tracheobronchial, nodular, and cystic or diffuse interstitial lung infiltration. Usually of AL (amyloid light chain) subtype, it may be localized or systemic, primary or secondary to a lymphoproliferative process. Very rare other diseases due to nonamyloid IgG deposits are described. Among the various lung manifestations of dysregulated states of humoral immunity, this article covers only those associated with the common variable immunodeficiency, IgG4-related disease, amyloidosis, and pulmonary light-chain deposition disease. Autoimmune connective-vascular tissue diseases or lymphoproliferative disorders are addressed in other chapters of this issue.

Chronic pulmonary aspergillosis complicating sarcoidosis.

Chronic pulmonary aspergillosis (CPA) complicating sarcoidosis (SA) is associated with high mortality, and there is a lack of clarity regarding the relative contributions of SA or CPA.This was a retrospective single-centre study on CPA-SA.In total, 65 patients (44 men), aged 41.4±13.5 and 48.3±11.9 years at the time of SA and CPA diagnoses, respectively, were included between 1980 and 2015. Of these, 64 had fibrocystic SA, most often advanced, with composite physiological index (CPI) >40 (65% of patients) and pulmonary hypertension (PH) (31%), and 41 patients (63%) were treated for SA (corticosteroids or immunosuppressive drugs). Chronic cavitary pulmonary aspergillosis (CCPA) was the most frequent CPA pattern. Regarding treatment, 55 patients required long-term antifungals, 14 interventional radiology, 11 resection surgery and two transplantation. Nearly half of the patients (27; 41.5%) died (mean age 55.8 years); 73% of the patients achieved 5-year survival and 61% 10-year survival. Death most often resulted from advanced SA and rarely from haemoptysis. CPI, fibrosis extent and PH predicted survival. Comparison with paired healthy controls without CPA did not show any difference in survival, but a higher percentage of patients had high-risk mould exposure.CPA occurs in advanced pulmonary SA. CPA-SA is associated with high mortality due to the underlying advanced SA rather than to the CPA. CPI, fibrosis extent and PH best predict outcome.

Efficacy and Tolerance of Anti-Tumor Necrosis Factor α Agents in Cutaneous Sarcoidosis: A French Study of 46 Cases.

Importance: Evidence for the long-term efficacy and safety of anti-tumor necrosis factor α agents (anti-TNF) in treating cutaneous sarcoidosis is lacking. Objective: To determine the efficacy and safety of anti-TNF in treating cutaneous sarcoidosis in a large observational study. Design, Setting, and Participants: STAT (Sarcoidosis Treated with Anti-TNF) is a French retrospective and prospective multicenter observational database that receives data from teaching hospitals and referral centers, as well as several pneumology, dermatology, and internal medicine departments. Included patients had histologically proven sarcoidosis and received anti-TNF between January 2004 and January 2016. We extracted data for patients with skin involvement at anti-TNF initiation. Main Outcomes and Measures: Response to treatment was evaluated for skin and visceral involvement using the ePOST (extra-pulmonary Physician Organ Severity Tool) severity score (from 0 [not affected] to 6 [very severe involvement]). Epidemiological and cutaneous features at baseline, efficacy, steroid-sparing, safety, and relapses were recorded. The overall cutaneous response rate (OCRR) was defined as complete (final cutaneous ePOST score of 0 or 1) or partial response (ePOST drop ≥2 points from baseline but >1 at last follow-up). Results: Among 140 patients in the STAT database, 46 had skin involvement. The most frequent lesions were lupus pernio (n = 21 [46%]) and nodules (n = 20 [43%]). The median cutaneous severity score was 5 and/or 6 at baseline. Twenty-one patients were treated for skin involvement and 25 patients for visceral involvement. Reasons for initiating anti-TNF were failure or adverse effects of previous therapy in 42 patients (93%). Most patients received infliximab (n = 40 [87%]), with systemic steroids in 28 cases (61%) and immunosuppressants in 32 cases (69.5%). The median (range) follow-up was 45 (3-103) months. Of the 46 patients with sarcoidosis and skin involvement who were treated with anti-TNF were included, median (range) age was 50 (14-78) years, and 33 patients (72%) were women. The OCRR was 24% after 3 months, 46% after 6 months, and 79% after 12 months. Steroid sparing was significant. Treatment was discontinued because of adverse events in 11 patients (24%), and 21 infectious events occurred in 14 patients (30%). Infections were more frequent in patients treated for visceral involvement than in those treated for skin involvement (n = 12 of 25 [48%] vs n = 2 of 21 [9.5%], respectively; P = .02). The relapse rate was 44% 18 months after discontinuation of treatment. Relapses during treatment occurred in 35% of cases, mostly during anti-TNF or concomitant treatment tapering. Conclusions and Relevance: Anti-TNF agents are effective but suspensive in cutaneous sarcoidosis. The risk of infectious events must be considered.

Efficacy and safety of tumor necrosis factor antagonists in refractory sarcoidosis: A multicenter study of 132 patients.

INTRODUCTION: The off-label use of TNF antagonists in refractory sarcoidosis is increasingly reported but data on their efficacy and safety are still insufficient. OBJECTIVE: To report on efficacy and safety of TNF antagonists in severe and refractory sarcoidosis. METHODS: Examination of retrospective demographic, clinical, therapeutic, and adverse event data on 132 sarcoidosis patients (58% women; mean (min-max) age = 45.5 (14-78) years) given TNF antagonists (mainly infliximab, 91%) and investigation of response-linked factors. RESULTS: The overall clinical response (complete and partial) rate was 64%. TNF-antagonist efficacy (i.e., significant decrease of the ePOST score) was noted in cases with neurologic, heart, skin, and upper respiratory tract involvements. No significant difference in efficacy was found between anti-TNF used alone and TNF with immunosuppressant. The use of anti-TNF allowed reducing prednisone dosage at end of follow-up (p < 0.001). Adverse events were observed in 52% of the patients; they included infections (36%) and allergic reactions (8%) and required treatment interruption in 31 cases (23%). When TNF antagonists were interrupted, 13 patients experienced relapses within 14 months on average (median follow-up: 20.5 months). CONCLUSION: TNF antagonists were efficacious in about two-thirds of patients with severe/refractory sarcoidosis but their use led to a high rate of adverse events.

Long-term outcomes of refractory neurosarcoidosis treated with infliximab.

Central nervous system localizations of sarcoidosis may be refractory to conventional treatment such as steroids and immunosuppressive drugs. Infliximab, a TNF-α antagonist chimeric antibody, has been shown to be effective for treatment of these localizations. The aim of this study was to evaluate the efficacy and safety, in particular the long-term outcomes, of the use of infliximab for the treatment of neurosarcoidosis. We retrospectively reviewed medical records of patients with neurosarcoidosis who had been treated with infliximab between 2009 and 2015. All patients had histologically proven non-caseating granulomas. Eighteen patients with histologically proven sarcoidosis were included in this study. All had neurological involvement consisting of meningeal (n = 16), cerebral (n = 10), spinal cord (n = 6), and/or optic nerve (n = 5) involvement. Sixteen patients had previously received at least one immunosuppressive drug in addition to corticosteroids, including cyclophosphamide in 11 patients. All patients received treatment with infliximab (3-7.5 mg/kg) associated with corticosteroids (n = 18), low-dose methotrexate (n = 15), azathioprine (n = 2), or mycophenolate (n = 1). Sixteen out of 18 patients improved clinically (initial median modified Rankin scale score of 3, final median score of 1; p < 0.0001). At 6 months after initiation of infliximab, six patients obtained complete remission (33%), ten attained partial remission (56%), and two had stable disease (11%). The median follow-up time was 20 months (range 6-93). Nine patients relapsed during follow-up (50%). Eight patients developed toxic side effects and seven of these side effects were infectious events. Infliximab is an efficacious treatment of refractory neurosarcoidosis. However, relapses frequently occurred during follow-up.

Efficacy and safety of TNF antagonists in ocular sarcoidosis: data from the French registry STAT.

Backgroung: This study investigated the efficacy and safety of TNF antagonists in sarcoid uveitis in unselected cases. Design: This is a multicentre study on patients with sarcoidosis who received TNF antagonists in pneumology and internal medicine departments in France. We present here the subgroup of patients with biopsy-proven sarcoid uveitis included in the nationwide registry STAT (Sarcoidosis treated with TNF AnTagonists). Results: Among the 132 patients included in this multicenter study, 18 patients with refractory uveitis were treated as a first-line TNF antagonist with infliximab (n=14), adalimumab (n=3) and certolizumab (n=1). Before anti-TNF initiation, the median duration of sarcoidosis was 42 months and 83% of the patients have been treated with at least one immunosuppressive drug. Six patients switched for a second-line TNF antagonist. After a mean time under treatment of 29 months, the treatment resulted in a significant decrease of the ophthalmic extrapulmonary Physician Organ Severity Tool (ePOST) (mean score: 4.2 vs. 2.6) scores and a steroid sparing effect (29.4±20.7 vs. 6.2±5.2 mg/d). Overall, the ophthalmic response, either complete or partial, was 67%. Nine patients (50%) presented adverse events, including severe infectious complications in 5 patients, which required anti-TNF treatment interruption in 6 cases (33%). Among the 7 responder patients who discontinued anti-TNF therapy, 71% relapsed. Finally, 12 patients (67%) could continue TNF antagonist treatment. Conclusions: TNF antagonists were efficient in 67% of biopsy-proven refractory sarcoid uveitis. Severe adverse events, mainly infectious complications, were frequent. The high frequency of relapses after anti-TNF-α discontinuation requires a close patient follow-up thereafter. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 74-80).

Efficacy and safety of infliximab therapy in refractory upper respiratory tract sarcoidosis: experience from the STAT registry.

Background: Upper respiratory tract (URT) involvement in sarcoidosis may be refractory to corticosteroids and immunosuppressants. Whether TNF-antagonists are efficient and safe in such phenotype is unknown. Methods: STAT is a French national drug registry including patients presenting sarcoidosis treated with TNF alpha antagonists. All cases of biopsy-proven sinonasal and laryngeal sarcoidosis were extracted and retrospectively analyzed from July 2014 to July 2015. Results: Twelve patients presenting biopsy-proven sarcoidosis with URT involvement were included in the STAT registry. Infliximab appeared effective in decreasing URT symptoms, as assessed by a significant decrease of the e-POST (extra-pulmonary Physician Organ Severity Tool) (1.5 [0-2] vs 5 [1.5-5], p=0.03) and a corticosteroids-sparing effect (7.5mg per day [5-10] vs 17.5 mg per day [7.5-20], p=0.04) at the end of follow-up. Conclusions: TNF-antagonists may be an efficient treatment of refractory URT manifestations and should be discussed when prolonged or high dosages of corticosteroids despite immunosuppressive therapy are required. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 343-351).