Background - Corticosteroids suppress disease activity in pulmonary sarcoidosis and their use produces symptomatic, radiographic, and functional improvement. There is, however, uncertainty regarding their effects on the overall natural history of the condition and long term benefit is unproven.Methods - Patients with pulmonary radiographic shadowing due to sarcoidosis were recruited in a multicentre study. Those who, in the first six months after entry to the study, neither required prednisolone for symptoms nor showed radiographic improvement were allocated at six months to receive either long term steroid treatment (group L) or selective treatment (group S), with regular assessment over the subsequent five years. Patients in group L were scheduled to receive steroid treatment for at least 18 months with the policy of achieving and maintaining maximal radiographic clearing, while in group S treatment was reserved for use only if warranted by later development of symptoms or deteriorating lung function. Symptoms, radiographic appearances, and respiratory function were assessed periodically during the study.Results - One hundred and forty nine patients were followed: 33 required prednisolone for troublesome symptoms within six months of entry and 58 showed radiographic improvement over this period. The remaining 58 patients were allocated to groups L (n = 27) and S (n = 31). Patients in group L showed greater improvements in symptoms, respiratory function, and radiographic appearances than those in group S, although the differences were not large. After adjusting for differences at the time of allocation, the average difference in vital capacity between groups L and S at final assessment was 9% of the predicted value. Side effects of treatment were frequent but usually mild, necessitating withdrawal in only two individuals.Conclusions - After excluding those individuals who required steroids for control of symptoms, approximately half of the remaining patients with sarcoidosis and pulmonary shadowing showed spontaneous radiographic improvement during six months of observation. In those in whom the radiograph failed to improve, prolonged steroid treatment with the aim of optimising radiographic appearances resulted in a significantly better long term functional outcome.

Because sarcoidosis resembles tuberculosis clinically and histologically, it has been suggested that mycobacteria might have a role in the pathogenesis of the disorder. Mycobacteria have not been found in sarcoid tissues by conventional culture techniques, so we have used a liquid-phase hybridisation method to see whether we could detect mycobacterial rRNA in such tissues. RNA was extracted from five sarcoid and five normal spleens. Extracts were assayed by liquid-phase DNA/RNA hybridisation with a DNA probe specific for the rRNA of the Mycobacterium tuberculosis complex. Hybridisation obtained with the sarcoid spleens, from which mycobacteria were neither seen on microscopy nor cultured with standard methods, was 4.8 times higher than that with normal spleens (p less than 0.001). Our demonstration of mycobacterial nucleic-acid components in sarcoid splenic tissues supports the notion that mycobacteria play a part in the cause of sarcoidosis.

Twenty six patients with sarcoidosis of recent onset or with severe progressive disease were studied for evidence of retroviral infection. Peripheral blood mononuclear cells (PBMC) were cultured in vitro and stimulated with phytohaemagglutinin and interleukin-2. Induction of syncytia (SI) and production of reverse transcriptase (RT) were sought as indicators of possible retroviral infection. PBMC from two patients showed syncytia formation and in one of these two there was associated production of low levels of reverse transcriptase. The remaining patients showed neither RT nor SI activity. The predominantly negative results of this study indicate that sarcoidosis is unlikely to be of retroviral aetiology; however, cell populations from sites of active disease should be studied before drawing this conclusion.

Granuloma formation in patients with sarcoidosis may be evoked by the intradermal injection of homogenised sarcoid tissue (the Kveim reaction). Attempts to demonstrate an in vitro counterpart of the reaction have been unsuccessful. The cytokine interleukin-2 (IL-2) enhances immune responses in vivo and in vitro. We report here an attempt to amplify the Kveim reaction by the addition of IL-2. We studied the effect of Kveim reagent on the proliferative responses of peripheral blood mononuclear cells (PBMC) in the presence or absence of exogenous IL-2. Twenty-eight patients were studied and 14 healthy subjects served as controls. PBMC were cultured, in vitro, in the presence of Kveim reagent. Recombinant IL-2 or both of these combined. Proliferative responses were measured by [3H]-thymidine incorporation. The response of patients' PBMC in the presence of Kveim reagent at a dilution of 1:40 was significantly below the unstimulated response (P less than 0.01). Kveim reagent at a dilution of 1:40 also inhibited the proliferative response of patients PBMC to IL-2 (P less than 0.005); greater dilutions (1:100 and 1:1000) of Kveim reagent were not inhibitory. Responses of PBMC from control subjects (both unstimulated and IL-2 generated) were reduced in the presence of Kveim reagent, however, these reductions were not statistically significant.

The technique of antigen immunoblotting for detection of specific immunoglobulin G (IgG), using Kveim material as antigen, was applied to paired sera and cerebrospinal fluid from 11 patients with definite neurosarcoidosis, 9 patients with definite sarcoidosis and suspected neurosarcoidosis, 22 patients with possible neurosarcoidosis and 16 patients with other neurological disorders, including multiple sclerosis and optic neuritis. Six of the 11 (55%) patients with neurosarcoidosis, none of the 9 patients with definite sarcoidosis and suspected neurosarcoidosis, 5 of the 22 (23%) with possible neurosarcoidosis, and none of the control patients had local synthesis of specific IgG reacting with Kveim material at some stage in the disease. Six of the 8 (75%) patients with definite neurosarcoidosis who had never received steroids or immunosuppressants had local synthesis of Kveim-specific IgG. Local synthesis of Kveim-specific IgG was not found in patients who had received in the past, or were still receiving, immunomodulating agents, and local synthesis was abolished when such treatment was introduced to those patients who had been positive. Those patients whose cerebrospinal fluid showed local synthesis of oligoclonal total IgG were more likely to have local synthesis of Kveim-specific IgG, but not necessarily in an oligoclonal fashion. Immunoblotting, using Kveim material, may thus be a useful adjunct for the investigation of suspected neurosarcoidosis.

The Kveim test provides a useful model for the ultrastructural study of developing epithelioid cell granulomas in man. We present a controlled prospective study in which 140 patients with possible sarcoidosis had two simultaneous Kveim tests, one being biopsed at a varying interval and the other at the usual 28 days: 52 patients showed a positive test. Controls were provided by the 88 negative tests, Kveim biopsis from 12 healthy subjects, and biopsies of normal spleen injection sites in a further 12 sarcoid patients. In all three groups the initial response (3 to 5 days) was macrophage influx. From 8 to 10 days, in developing positive tests only, mononuclear cells with abundant rough endoplasmic reticulum appeared. Mature epithelioid cells were seen at 12 to 14 days, when lymphocyte numbers and lymphocyte-histiocyte interactions were at a maximum. Epithelioid cells showed marked secretory activity; the ultrastructural features of the developing epithelioid cell vacuoles are identical to those seen in exocrine cells. Mast cells are not involved in the development of granulomas.

Interleukin-2 has been reported to enhance the immune response in diseases characterised by defective cell mediated immunity. The effect of exogenous recombinant interleukin-2 was studied on the proliferative and cytotoxic responses of peripheral blood mononuclear cells from 39 patients with sarcoidosis and 14 healthy control subjects. The proliferative response to purified protein derivative was smaller in patients than in control subjects (p less than 0.001) whereas the response to 80 U interleukin-2 alone and to purified protein derivative and interleukin-2 did not differ significantly between the two groups. In addition, in eight patients but no control subjects tritiated thymidine incorporation induced by the combination of purified protein derivative and interleukin-2 was more than twice the sum of that induced by purified protein derivative and interleukin separately. Cytotoxic activity occurring spontaneously and induced by purified protein derivative and interleukin-2 in blood mononuclear cells was significantly less for patients with sarcoidosis than for control subjects (p less than 0.05 spontaneous, less than 0.001 purified protein derivative induced, less than 0.02 interleukin induced). Synergism between antigen and interleukin did not occur with respect to the cytotoxic response in either patients or controls. Defective interleukin-2 production may contribute to, but does not entirely explain, the functional abnormalities of peripheral blood lymphocytes from patients with sarcoidosis.

Of some 750 sarcoidosis patients, 27 were found to have involvement of their nasal mucosa. Most had multisystem disease, which was usually chronic. Nasal stuffiness or blockage and crusting were the major symptoms, and were usually present at the first presentation with sarcoidosis. The larynx was involved in five cases. The Kveim test was positive in twelve of the fourteen patients in whom it was performed, serum angiotensin converting enzyme was frequently elevated and sinus radiographs were often abnormal. Topical medication improved symptoms in some patients, but the majority required systemic corticosteroids. It was possible to withdraw medication completely after seven years in only one patient. Relapse was encountered during reduction of dosage in other patients. Random biopsy of macroscopically normal nasal mucosa did not yield histological support for a diagnosis of sarcoidosis in twelve out of thirteen patients, but upper respiratory tract lymphoid tissue may contain granulomas in patients with sarcoidosis.

Conference Abstract| December 01 1987 Enhancement of Proliferative Response to Antigen by Inerleukin-2: Similar Effects in Sarcoidosis Patients and Controls D J Lyons; D J Lyons 1Clinical Research Centre Watford Road Middlesex Search for other works by this author on: This Site PubMed Google Scholar D N Mitchell; D N Mitchell 1Clinical Research Centre Watford Road Middlesex Search for other works by this author on: This Site PubMed Google Scholar E B Mitchell; E B Mitchell 1Clinical Research Centre Watford Road Middlesex Search for other works by this author on: This Site PubMed Google Scholar G L Asherson G L Asherson 1Clinical Research Centre Watford Road Middlesex Search for other works by this author on: This Site PubMed Google Scholar Clin Sci (Lond) (1987) 73 (s17): 33P. https://doi.org/10.1042/cs073033Pb Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation D J Lyons, D N Mitchell, E B Mitchell, G L Asherson; Enhancement of Proliferative Response to Antigen by Inerleukin-2: Similar Effects in Sarcoidosis Patients and Controls. Clin Sci (Lond) 1 December 1987; 73 (s17): 33P. doi: https://doi.org/10.1042/cs073033Pb Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 1987 The Biochemical Society and the Medical Research Society1987 Article PDF first page preview Close Modal You do not currently have access to this content.

Letters and Corrections1 January 1986Megaloblastic Anemia in SarcoidosisM. C. SWEATMAN, M.B., M.R.C.P., R. WILSON, M.B., M.R.C.P., D. N. MITCHELL, M.D., M.R.C.P.M. C. SWEATMAN, M.B., M.R.C.P.Search for more papers by this author, R. WILSON, M.B., M.R.C.P.Search for more papers by this author, D. N. MITCHELL, M.D., M.R.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-104-1-129_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: We report the case of a patient with sarcoidosis and macrocytic anemia attributable to megaloblastic changes in a bone marrow infiltrated by typical sarcoid granulomas. Extensive investigation failed to reveal any other cause for her megaloblastic anemia.A 41-year-old white woman presented with lethargy, breathlessness, and weight loss. Physical findings included jaundice, bruising, ankle edema, and hepatosplenomegaly. Laboratory studies showed hemoglobin, 6.4 g/dL; erythrocyte count, 1.96 X 1012/L; mean cell volume, 101 fL; leukocyte count, 1.7 X 109/L; platelets, 87 X 109/L; and reticulocytes, 0.8%. A blood film showed macrocytosis, anisocytosis, poikilocytosis, and hypersegmented neutrophils. The clotting...References1. SCADDINGMITCHELL JD. Sarcoidosis. 2nd ed. London: Chapman and Hall Medical; 1985. CrossrefGoogle Scholar2. WEBBMITCHELLBRADSTREETSALSBURY ADCA. Splenomegaly and splenectomy in sarcoidosis. J Clin Pathol. 1979;32:1050-3. CrossrefMedlineGoogle Scholar3. TINKERVISWANATHANLAUFERMARGOLIS MBHI. Acute appendicitis and pernicious anemia as complications of gastrointestinal sarcoidosis. Am J Gastroenterol. 1984;79:868-72. MedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Cardiothoracic Institute and Medical Research Council Tuberculosis and Chest Diseases Unit London SW3 6HP England PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 January 1986Volume 104, Issue 1Page: 129-129KeywordsGranulomasHemoglobinHepatosplenomegalyMegaloblastic anemiaNeutrophilsPlateletsResearch laboratoriesReticulocytesSarcoidosisWeight loss Issue Published: 1 January 1986 PDF DownloadLoading ...

Human bone marrow cells derived from multiple sclerosis (MS) and control patients were screened for a number of virus antigens by the fluorescent antibody technique using monoclonal antibodies. The results showed that antigens of the paramyxovirus, simian virus 5, were present in about 60% of MS and 25% of control bone marrows. About 25% of the MS and 50% of control bone marrows were found to contain nucleoprotein antigen of the human parainfluenza types 1 and 3. These experiments demonstrated that paramyxoviruses can persist in human tissues possibly in a defective or repressed state.

Simian virus 5 (SV5) isolates derived after co-cultivation of human bone marrow aspirates of multiple sclerosis (MS) patients were shown by immunoprecipitation, cross-neutralization and haemagglutination inhibition techniques to be similar antigenically but not identical to the prototype strain. Analyses of human sera (MS and control) showed that about 20% contained neutralizing antibodies to SV5 and immunoprecipitated the specific SV5 HN polypeptide. A competition assay using a specific SV5 monoclonal antibody confirmed that a human serum containing such neutralizing activity also blocked a specific SV5 epitope whereas another human serum with demonstrable antibodies to the related human parainfluenza virus type 2 did not block this epitope. These tests therefore suggested that SV5 can infect humans. However, there was no indication, on the basis of these tests, of any aetiological relationship of the SV5 infection to the induction of MS.