Reproductive and hormonal risk factors for sarcoidosis: a nested case-control study.

BACKGROUND: Sarcoidosis incidence peaks in females around the fifth decade of life, which coincides with menopause, suggesting hormonal factors play a role in disease development. We investigated whether longer exposure to reproductive and hormonal factors is associated with reduced sarcoidosis risk. METHODS: We conducted a matched case-control study nested within the Mammography Screening Project. Incident sarcoidosis cases were identified via medical records and matched to controls on birth and questionnaire date (1:4). Information on hormonal factors was obtained through questionnaires prior to sarcoidosis diagnosis. Multilevel modelling was used to estimate adjusted odds ratios with 95% credible intervals (OR; 95% CI). RESULTS: In total, 32 sarcoidosis cases and 124 controls were included. Higher sarcoidosis odds were associated with older age at menarche (OR 1.19: 95% CI 0.92-1.55), natural menopause versus non-natural (OR 1.53: 95% CI 0.80-2.93), later age at first pregnancy (OR 1.11: 95% CI 0.76-1.63) and ever hormone replacement therapy (HRT) use (OR 1.40: 95% CI 0.76-2.59). Lower odds were associated with older age at menopause (OR 0.90: 95% CI 0.52-1.55), longer duration of oral contraceptive use (OR 0.70: 95% CI 0.45-1.07), longer duration of HRT use (OR 0.61: 95% CI 0.22-1.70), ever local estrogen therapy (LET) use (OR 0.83: 95% CI 0.34-2.04) and longer duration of LET use (OR 0.78: 95% CI 0.21-2.81). However, the CIs could not rule out null associations. CONCLUSION: Given the inconsistency and modest magnitude in our estimates, and that the 95% credible intervals included one, it still remains unclear whether longer estrogen exposure is associated with reduced sarcoidosis risk.

Case Report: Immune-Related Toxicity During Adjuvant Treatment With BRAF Plus MEK Inhibitors in a Melanoma Patient.

Adjuvant treatment of operated melanoma has deeply changed in the last few years with the introduction of immune-checkpoint inhibitors and BRAF/MEK inhibitors. Sarcoidosis is a systemic inflammatory disease causing non-caseous granulomatous reactions. Sarcoid-like granulomatous reactions have been reported in patients with advanced melanoma, mostly related to immunotherapy with immune-checkpoint inhibitors. We report a case of a 38-year-old woman with stage III operated melanoma treated with adjuvant BRAF plus MEK inhibitors, who developed sarcoidosis-like syndrome with systemic involvement, resolved after discontinuation of treatment. The occurrence of immune-related toxicity with the use of MAPK inhibitors supports the hypothesis that this class of drugs may also have an immunological effect, and that the long-term efficacy of adjuvant MAPK inhibitors may be due to their immunological function.

Sarcoidosis Following Anti-PD-1 and Anti-CTLA-4 Therapy for Metastatic Melanoma.

Immune checkpoint inhibitors represent the newest treatment for stage IV melanoma. These agents are generally well tolerated, however severe immune-related adverse effects have been noted in a small, but clinically significant percentage of patients. Specifically, sarcoidosis is a known potential complication following anti-CTLA-4 therapy. We present 2 cases of pulmonary and cutaneous sarcoidosis developing in patients with stage IV melanoma. Both patients were treated with ipilimumab and anti-PD-1 therapy, and both experienced good oncologic responses to treatment; neither had evidence of preexisting sarcoidosis. Of note, both patients developed sarcoidosis only after undergoing immune checkpoint inhibitor therapy. In 1 patient, sarcoidosis developed after initiation of anti-PD-1 therapy, 3 months after the last dose of anti-CTLA-4 monotherapy, suggesting a synergistic immune dysmodulating effect of both checkpoint inhibitors. Ultimately, both patients' symptoms and radiologic findings resolved with corticosteroid treatment, and both patients have tolerated retreatment with PD-1 inhibitors. Sarcoidosis is a rare complication of immune checkpoint inhibitors and can manifest with severe pulmonary manifestations. However, sarcoidosis in this setting is responsive to corticosteroids and does not necessarily recur with retreatment. It is yet unclear whether the development of sarcoidosis in these patients represents unmasking of preexisting autoimmune tendencies or is a marker of oncologic response.

Type-specific L1 virus-like particle-mediated protection of horses from experimental bovine papillomavirus 1-induced pseudo-sarcoid formation is long-lasting.

Equine sarcoids are common therapy-resistant skin tumours induced by bovine papillomavirus type 1 or 2 (BPV1, BPV2) infection. We have previously shown that prophylactic vaccination with BPV1 L1 virus-like particles (VLPs) efficiently protects horses from experimental BPV1-induced pseudo-sarcoid development. Here, we assessed BPV1 L1 VLP vaccine-mediated long-term protection from experimental tumour formation in seven horses 5 years after immunization with three different doses of BPV1 L1 VLPs, and three unvaccinated control animals. Horses were challenged by intradermal inoculation with infectious BPV1 virions at 10 sites on the neck (106 virions per injection). In vaccinated horses, BPV1 challenge did not result in any apparent lesions irrespective of vaccine dosage and BPV1-neutralizing antibody titres that had dropped considerably over time and below the detection limit in one individual. Control horses developed pseudo-sarcoids at all inoculation sites. We conclude that immunization of horses with BPV1 L1 VLPs induces long-lasting protection against experimental BPV1 virion-induced disease.

Appendectomy, tonsillectomy, and risk for sarcoidosis - A hospital-based case-control study in Japan.

BACKGROUND: The role of surgery in the onset of sarcoidosis is unclear. We investigated whether surgery is an internal environmental factor for sarcoidosis onset within the Japanese population. METHODS: We enrolled 222 patients diagnosed with sarcoidosis (78 men, 144 women) who were admitted to our department between 1984 and 2012. We also enrolled 529 control subjects (251 men, 278 women), who were matched for sex, age at admission, and year of admission. Surgical history, family history, and smoking status were evaluated. RESULTS: Multivariate analysis correlated history of appendectomy (OR, 1.55; 95% CI, 1.05-2.29) and tonsillectomy (OR, 2.79; 95% CI, 0.91-8.56) with the occurrence of sarcoidosis; other surgical procedures had no correlation. In women, appendectomy had a stronger association with sarcoidosis (OR, 1.69; 95% CI, 1.05-2.73), as opposed to that in men (OR, 1.39; 95% CI, 0.68-2.85). This association was greater in women aged ≥45 years than in those aged <45 years. There was a stronger correlation between tonsillectomy and sarcoidosis in women (OR, 3.30; 95% CI, 0.88-12.39), than in men (OR, 1.26; 95% CI, 0.10-16.52). ORs for sarcoidosis were 5.55 (95% CI, 2.02-15.27) and 0.97 (95% CI, 0.52-1.84) in women aged ≥45 years with a history of appendectomy at <20 years and ≥20 years, respectively, with the former being statistically significant. CONCLUSIONS: Appendix and tonsil removal was associated with sarcoidosis onset, suggesting their potential protective role against sarcoidosis development. Further studies are needed to minimize possible confounding factors.

Potential of a BPV1 L1 VLP vaccine to prevent BPV1- or BPV2-induced pseudo-sarcoid formation and safety and immunogenicity of EcPV2 L1 VLPs in horse.

We have previously shown that immunization of horses with bovine papillomavirus type 1 (BPV1) L1 virus-like particles (VLPs) is safe and highly immunogenic and that BPV1 and bovine papillomavirus type 2 (BPV2) are closely related serotypes. Here we evaluated the protective potential of a BPV1 L1 VLP vaccine against experimental BPV1 and BPV2 challenge and studied the safety and immunogenicity of a bivalent equine papillomavirus type 2 (EcPV2)/BPV1 L1 VLP vaccine. Fourteen healthy horses were immunized with BPV1 L1 VLPs (100 µg per injection) plus adjuvant on days 0 and 28, while seven remained unvaccinated. On day 42, all 21 horses were challenged intradermally at 10 sites of the neck with 107 BPV1 virions per injection. In analogy, 14 horses immunized twice with EcPV2 plus BPV1 L1 VLPs (50 µg each) and seven control animals were challenged with 107 BPV2 virions per injection. Immunization with BPV1 L1 VLPs alone induced a robust antibody response (day 42 median titre: 12 800), and BPV1-inoculated skin remained unchanged in 13/14 vaccinated horses. Immunization with the bivalent vaccine was safe, resulted in lower median day 42 antibody titres of 400 for BPV1 and 1600 for EcPV2 and conferred significant yet incomplete cross-protection from BPV2-induced tumour formation, with 11/14 horses developing small, short-lived papules. Control horses developed pseudo-sarcoids at all inoculation sites. The monovalent BPV1 L1 VLP vaccine proved highly effective in protecting horses from BPV1-induced pseudo-sarcoid formation. Incomplete protection from BPV2-induced tumour development conferred by the bivalent vaccine is due to the poorer immune response by immune interference or lower cross-neutralization titres to heterologous BPV2 virions.

[Current Therapeutic Approaches to Sarcoidosis]. / Aktuelle Therapieansätze der Sarkoidose.

Sarcoidosis represents a non-caseating, granulomatous disorder of unknown aetiology whose clinical manifestation is heterogeneous and frequently multisystemic. The portion of patients needing systemic treatment varies: though many patients may undergo spontaneous remission, organ-threatening courses demand systemic therapy. Corticosteroids are the first-line treatment option; however, disease´s progression and/or major corticosteroid side effects may require second- and third-line therapeutics. A current stepwise therapeutic algorithm to sarcoidosis that characterizes additive and alternative therapeutic agents is given in the following review.

Reproductive and hormonal factors in relation to incidence of sarcoidosis in US Black women: The Black Women's Health Study.

The authors assessed the relation of hormonal and pregnancy-related factors to the incidence of sarcoidosis in the Black Women's Health Study. On biennial questionnaires, participants (US black women aged 21-69 years at baseline) reported data on diagnoses of sarcoidosis, reproductive history, and medication use. Cox regression models, adjusted for age, education, geographic region, smoking, and body mass index, were used to estimate incidence rate ratios and 95% confidence intervals. During 694,818 person-years of follow-up from 1995 through 2009, 452 incident cases of sarcoidosis were identified. The incidence of sarcoidosis decreased as age at menopause increased (P-trend = 0.03). Both later age at first full-term birth and having a more recent birth were associated with a reduced incidence of sarcoidosis. In models that included both factors, the incidence rate ratios were 0.60 (95% confidence interval: 0.37, 0.97) for age at first birth ≥30 years versus <20 years (P-trend = 0.05) and 0.73 (95% confidence interval: 0.43, 1.24) for <5 years since last birth versus ≥15 years (P-trend = 0.15). No significant associations were observed with age at menarche, parity, lactation, oral contraceptive use, or female hormone use. These results suggest that later full-term pregnancy and longer exposure to endogenous female hormones may be related to a reduced risk of sarcoidosis.

[Bilateral recurrent blurred vision associated with halos around sources of light and headache]. / Beidseitiges, rezidivierendes Verschwommensehen mit Farbringen um Lichtquellen und Kopfschmerzen.

A 21-year-old male presented with headache and blurred vision associated with halos around sources of light. The visual acuity was slightly reduced and the intraocular pressure in the left eye was elevated to 44 mmHg and in the right eye to 49 mmHg. Slit lamp examination of the anterior segment revealed bilateral cells and a Tyndall phenomenon 2 +, several cell clumps adherent to the corneal endothelium, known as mutton-fat keratic precipitates and a circumscribed inflammatory infiltration of the right iris. The posterior segment of both eyes was normal. The cause of the presumed clinical diagnosis secondary open angle glaucoma due to anterior granulomatous uveitis was sarcoidosis, confirmed by elevated serological markers of angiotensin-converting enzyme (ACE), soluble interleukin-2 receptor (sIL-2R) and by pulmonary hilar lymphadenopathy. The local and systemic corticosteroid therapy was successful and also normalized the intraocular pressure.

Sarcoidosis y compromiso renal: reporte de un caso y revisión de la literatura científica / Sarcoidosis and kidney disease: a case report and review of the literature

Se presenta el caso de una mujer de 30 años, que presentaba síntomas respiratorios y constitucionales de dos meses de evolución. Se documentó exudado linfocitario y proteinuria, y se descartó tuberculosis y neoplasia maligna. Se le practicó biopsia pleuraly de ganglio linfático, que reportaron sarcoidosis. Se tomó biopsia renal por presencia de proteinuria con pruebas serológicas negativas, y se encontró glomerulonefritis membranosa secundaria. Se inició tratamiento con prednisolona...

We describe the case of a 30 years old female with a two month history of respiratory symptoms and malaise. A lymphocytic pleural effusion and proteinuria were documented,tuberculosis and malignancy were ruled out. Biopsy of lymph nodes and pleura confirmed sarcoidosis. Due to non-nephrotic proteinuria with negative serology tests, kidney biopsy was performed, showing secondary membranous glomerulonephritis. Treatment with prednisolone was started...

Is tobacco smoking protective for sarcoidosis? A case-control study from North India.

BACKGROUND: While tobacco smoking is commonly believed to be negatively associated with the occurrence of sarcoidosis, the relationship of environmental tobacco smoke (ETS) exposure with sarcoidosis is largely un-explored. We studied the impact of active smoking and ETS exposure on disease severity in newly diagnosed cases of sarcoidosis from India. METHODS: Data on demographic variables, smoking habits and exposure to environmental tobacco smoke (ETS) among non-smoker sarcoidosis patients was collected prospectively. Presence of smoking and ETS exposure were compared among cases and controls. Among the sarcoidosis patients, clinical manifestations, radiology, spirometry and histopathological grading of lung biopsy were compared between the smokers vs. non-smokers and ETS exposed vs. not-exposed. RESULTS: We studied 98 newly diagnosed cases of sarcoidosis and 196 age, sex and religion- matched healthy volunteers. The study group comprised of 62 (63%) men and 36 (37%) women. The prevalence of smoking was similar in cases and controls (12.2% vs. 15.3%, p = 0.48). Among the never smoker patients with sarcoidosis, 20 (23%) reported ETS exposure vis-a-vis 57 (34%) in the matched controls. A conditional logistic regression analyses showed insignificant negative association with active smoking (OR 0.75; 95% CI, 0.35-1.56) or ETS exposure (OR 0.58; 95% CI, 0.32-1.06) after adjusting for age, gender, religion, and education. There were no differences in the clinical manifestations, radiological staging, spirometry and histopathological grading of lung biopsy in any of the group comparisons studied. CONCLUSION: Smoking or ETS exposure may not have significant negative association with sarcoidosis. Also, tobacco smoke might not have any effect on the clinical behavior or disease severity in sarcoidosis. The belief that smoking is protective for sarcoidosis is not substantiated in this study and appears to be misfounded.

[Sarcoidosis, myasthenia gravis and anterior ischaemic optic neuropathy: severe side effects of adjuvant interferon-alpha-therapy in malignant melanoma?]. / System-sarkoidose, Myasthenia gravis und anteriore ischämische Optikusneuropathie: schwere Nebenwirkungen unter adjuvanter Interferon-alpha-Therapie bei malignem Melanom?

In dermato-oncology, interferon-alpha is widely used as treatment of cutaneous lymphoma and as adjuvant therapy in high risk malignant melanoma. With increasingly wide administration of interferon-alpha (IFN-alpha), not only early-onset side effects, such as influenza-like symptoms, but also uncommon late-onset side effects are being recognized. We present three patients with melanoma who developed rare side effects in the course of adjuvant IFN-alpha-therapy: sarcoidosis, myasthenia gravis and anterior ischaemic optic neuropathy. Based on current knowledge a causal relationship between these diseases and the administration of IFN-alpha can neither be affirmed or absolutely ruled out. Therefore special attention should be paid to such coincidences.

[New developments in mass roentgen studies]. / Neuordnung der Röntgenreihenuntersuchungen.

Since 1984 in the GDR the persons older than 40 years are summoned to participate in the mass X-ray examinations in a two-year sequence. The risk groups of tuberculosis are called up at shorter intervals, this also concerns younger people. To this belong patients with silicosis, so-called "healthy carriers of lesions", persons with contacts to patients suffering from tuberculosis, diabetics and the staff of tuberculosis hospitals and pathological institutes. Furthermore, persons working in national education, kindergartens and cattle-breeding are particularly controlled. Patients with chronic diseases of the respiratory tract need our increased attention.

[Is annual X-ray examination of the chest still justified in industrial medicine?]. / L'examen radiologique annuel du thorax est-il encore justifié en médecine du travail?

Between 1975 and 1979, 137.526 annual X-ray examinations of the chest were performed among the employees of a large Paris administration. Fifty-four cases of tuberculosis, 28 cases of sarcoidosis, 10 cases of bronchial carcinoma and 26 miscellaneous chest diseases were detected. This study confirms the inadequacy of radiological examination for detecting chronic obstructive bronchopulmonary conditions. The small proportion of tuberculosis (0.39 p.1000) and bronchial carcinoma (0.07 p.1000) revealed by this method suggests that it should be reserved to high risk patients.

[Mass radiography. The "pros and cons" of a classic method of preventive medicine (author's transl)]. / Röntgenreihenuntersuchungen. Das "Für" und "Wider" einer klassischen Methode der Präventivmedizin.

The relation of expense to benefit of mass radiography (RRU) can no longer be referred to the tuberculosis discovery rate. Far more frequently other thoracic diseases are detected, e.g. tumors, cardiovascular diseases, pneumoconiosis, sarcoidosis, etc. The prerequisite and therefore the immediate objective is the limitation to the defined and detectable group of risks so as to increase the detection rate. In combination with other prophylactic investigations the benefit of RRU can still be increased -- it provides a valuable insight into the epidemiology of different social diseases.