Extrapulmonary sarcoidosis

The clinical manifestations of sarcoidosis are extremely heterogeneous and overlap with a wide gamut of infectious and noninfectious granulomatous disorders. Prognosis of sarcoidosis is highly variable. Spontaneous remissions occur in nearly two thirds of patients, but chronic, progressive disease may result in severe sequelae. Fatalities occur in 1% to 4% of patients. Pulmonary manifestations typically dominate, but any organ can be affected. Skin, eye, and peripheral lymph nodes are each involved in 20% to 30% of patients. Clinically significant involvement of spleen, liver, bone, heart, kidney, or central nervous system occurs in 2% to 6% of patients. Asymptomatic involvement of these organs is far more common. We review the salient extrapulmonary features of sarcoidosis, and compare and contrast specific features that may mimic other etiologies.     

Oligoclonal banding of IgG in CSF, blood-brain barrier function, and MRI findings in patients with sarcoidosis, systemic lupus erythematosus, and Beh?et's disease involving the nervous system

A retrospective study of CSF and serum analysis from a total of 43 patients with sarcoidosis, 20 with systemic lupus erythematosus, and 12 with Beh?et's disease with neurological involvement found local synthesis of oligoclonal IgG using isoelectric focusing and immunoblotting in 51%, 25%, and 8% respectively at some stage in their disease. Blood-brain barrier breakdown, when assessed with an albumin ratio found 47% of patients with sarcoidosis, 30% of those with systemic lupus erythematosus, and 42% of patients with Beh?et's disease exhibiting abnormal barrier function at some time. Serial CSF analysis showed that clinical relapses were associated with worsening barrier function and in some patients the development of local oligoclonal IgG synthesis; conversely steroid treatment led to a statistically significant improvement in barrier function, and in two patients a loss of oligoclonal IgG bands. A higher proportion of patients had MRI abnormalities than oligoclonal IgG or blood-brain barrier breakdown, MRI being abnormal in 16 of 19 patients with sarcoidosis, three of four patients with systemic lupus erythematosus, and seven of nine patients with Beh?et's disease, although this may have been due to temporal factors. In the differential diagnosis of chronic neurological disorders, locally synthesised oligoclonal IgG cannot distinguish between diseases, but the loss of bands seen in two patients contrasts with what is seen in multiple sclerosis, and thus may be a useful diagnostic clue.     

Renal manifestations in sarcoidosis

Clinically distinct renal disease is said to be rare in sarcoidosis, but autopsy reveals an incidence of renal involvement is 23 or 26% in Japanese studies. There are three categories of renal disease in sarcoidosis: 1) renal changes by abnormal calcium metabolism, 2) interstitial nephritis or granulomatous nephritis and 3) glomerulonephritis. Some investigators add renal angiitis to the three categories. In some patients without clinical renal disorders, renal involvement is discovered by chance at the time of autopsy or renal biopsy. Renal disease may develop during the course of sarcoidosis, preceding the diagnosis of sarcoidosis, or may be found simultaneously with extrarenal involvements at the time of diagnosis. Renal involvement should always be considered for exact diagnosis and appropriate treatment.     

Neurologic manifestations of sarcoidosis

126 patients with histologically verified mediastinal-pulmonary legions were examined in terms of neurologic manifestations of sarcoidosis. Systemic psychoneurologic observation of all patients was performed by continuous method. Neurologic disorders were nonmalignant, chronic, latent or transitory. Stable, acute or severe manifestations were registered quite seldom. Sensory, autonomic, neuroendocrine and neuropsychologic disorders prevailed in clinical picture.     

Thyroid disorders and sarcoidosis

Thyroid disorders were detected in 3.7% of our 269 cases of sarcoidosis histologically confirmed. This is close to the rate in the literature. As a probability of this complication that some of closely allied autoimmune disorder may relate both disease, except by chance. In 2 of our cases, these diseases appeared alternately as follows. A 49 years old woman suffered from granular-hard struma with hypothyroid from 4 years ago when sarcoidosis had completely healed. On the other side, a 55 years old woman had the apparent struma for about 16 years from her 6 years of age and gradually disappeared after the signs of sarcoidosis became apparent. She also had a Basedow's patient in her family.     

Detection of antibodies to Borrelia species among patients with confirmed sarcoidosis in a region where Lyme disease is nonendemic

BACKGROUND: Lyme disease is a multisystemic disorder caused by the spirochete Borrelia burgdorferi, while sarcoidosis is a multisystemic granulomatous disease of unknown etiology. The purpose of this study was to evaluate the relationship between Lyme disease and sarcoidosis. METHODS: We examined the seroprevalence of antibody to Borellia species in patients with sarcoidosis. We performed the enzyme-linked immunosorbent assay, using three Japanese Borrelia species in addition to B. burgdorferi, and dotblot analysis using purified Borrelia-specific proteins in 38 patients with histopathologically confirmed sarcoidosis and 80 healthy controls. RESULTS: Two patients (5.3%) were positive for antibodies to Borrelia species according to one or both assays, and one (1.2%) healthy control was positive. In both patients it was suspected that Borrelia infection had developed prior to the development of sarcoidosis. CONCLUSION: Borrelia species were thought not to be responsible for the development of sarcoidosis in a nonendemic region in Japan. Since clinical manifestations of Lyme disease share certain similarities with those seen in sarcoidosis, ophthalmologists should be aware of the need to differentiate between the two diseases and the need for prompt treatment in each case.     

Methotrexate treatment for sarcoid-associated panuveitis

OBJECTIVE: To determine the safety and efficacy of low-dose methotrexate (MTX) for sarcoid-associated panuveitis. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Twenty eyes from 11 patients were analyzed. Eight patients had sarcoidosis. Three patients were clinically suspected of sarcoidosis despite negative laboratory testing. All charts of patients with sarcoidosis and idiopathic uveitis seen by the Duke Uveitis Service from 1989 to 1997 were retrospectively reviewed. Those with sarcoid-associated or sarcoid-suspected panuveitis treated with MTX with a minimum of 6 months of follow-up were studied. INTERVENTION: Low-dose MTX was administered to patients weekly and patients were followed with serial ophthalmologic and medical examinations. MAIN OUTCOME MEASURES: Visual acuity, oral and topical corticosteroid requirements, anterior chamber inflammation, and ability to undergo successful cataract extraction were used to measure the efficacy of MTX therapy. RESULTS: After MTX treatment was initiated, 90% of eyes had preserved or improved visual acuity. Mean initial Snellen visual acuity was 20/62 and mean final acuity was 20/40 (P = 0.044). Of those patients initially requiring oral corticosteroids, the dosage was decreased in 100%, and they were completely discontinued in 86%. The mean initial oral corticosteroid dose was 26.6 mg and the mean final dose was 1.5 mg (P = 0.012). Topical corticosteroids were decreased in 63% of eyes. The mean initial use was once every 1.6 hours, and the mean final use was once every 3.9 hours (P = 0.001). Ninety-five percent of eyes had stabilized or decreased inflammation. The mean initial inflammation score was 1.2, and the mean final score was 0.5 (P = 0.007). Five of six eyes previously unable to have cataract extraction because of uncontrolled inflammation became quiet on MTX and underwent surgery. One hundred percent of these eyes had improved vision after surgery. Side effects were mild and transient or reversible. CONCLUSION: Low-dose MTX is an effective and safe adjunct to treat chronic sarcoid-associated panuveitis.     

The Norwegian Polio Study 1994: a nation-wide survey of problems in long-standing poliomyelitis

BACKGROUND: Sarcoidosis is a multisystemic granulomatous disease of unknown etiology, while Lyme borreliosis is a multisystemic disorder caused by Borrelia burgdorferi. The purpose of this study is to evaluate the relationship between sarcoidosis and Lyme borreliosis in a region of Japan where Lyme borreliosis is endemic. METHODS: We determined the seroprevalence of anti-Borrelia burgdorferi antibodies as well as antibodies three Japanese Borrelia strains by enzyme-linked immunosorbent assay and dotblot assay using purified Borrelia-specific proteins in 46 patients with confirmed sarcoidosis and 150 controls (50 disease controls and 100 healthy controls) in Hokkaido, the affected region. RESULTS: Fifteen patients with sarcoidosis (32.6%) tested positive for Borrelia spirochete in both assays, compared with two disease controls (4.0%) and two healthy controls (2.0%). The seroprevalence of anti-Borrelia antibodies in patients with sarcoidosis was much higher in the affected region than in the region in our previous study were Lyme borreliosis is non-endemic. CONCLUSION: In a region where Lyme borreliosis is endemic, Borrelia infection may be partially associated with sarcoidosis.     

Surface ultrastructure of human dermis and wounds

BACKGROUND: Intermediate uveitis is characterized by vitreal inflammation with associated inflammation of the vitreous base and peripheral anterior retina and choroid. It may be found as an isolated and idiopathic condition or in association with systemic disorders such as multiple sclerosis and sarcoidosis. OBJECTIVE: To identify the clinical features of intermediate uveitis and assess its association with systemic diseases. METHODS: Retrospective study of 83 patients presenting with intermediate uveitis between 1970 and 1991. RESULTS: Evidence of systemic disorders was found in 26 of 83 patients (31.3%). Of these 26 patients, 10 had presumed sarcoidosis, 6 had multiple sclerosis, 2 had isolated optic neuritis, 2 had inflammatory bowel disease, 4 had isolated thyroid abnormalities, and 2 had histories suggestive of Epstein-Barr virus infection. Associated ocular findings included cystoid macular edema, peripheral retinal perivascular sheathing, cataracts, posterior vitreous detachment, fine keratic precipitates, preretinal macular fibrosis, retinal tears, retinal detachment, and optic disc edema. CONCLUSIONS: Patients with intermediate uveitis may have associated systemic diseases and should have careful follow-up with regular systemic evaluation.     

Measurement of T cell subsets in bronchoalveolar lavage fluid for diagnosis of pulmonary sarcoidosis

Pulmonary sarcoidosis is characterized by the accumulation in the lower respiratory tract of large numbers of activated CD4 T cells and elevated ratio of CD4/CD8 in bronchoalveolar lavage fluid (BALF). To study the value of CD4/CD8 ratio in BALF in the diagnosis of pulmonary sarcoidosis, we measured T cell subsets in BALF of patients with pulmonary sarcoidosis. The CD4/CD8 ratio in the patients (7.5 +/- 4.3) was significantly higher than that of the controls (2.1 +/- 0.7). The sensitivity and specificity of CD4/CD8 ratio in BALF for the diagnosis of sarcoidosis were 86% and 100%, respectively. We found that the CD4/CD8 ratio in BALF plays an important role in the diagnosis of pulmonary sarcoidosis. The analysis of CD4 in BALF may be useful in assessing the activity of sarcoidosis. The measurement of the CD4/CD8 ratio may be used to determine prognosis of pulmonary sarcoidosis.     

Clinical correlates of granulomas in muscle

We evaluated the clinical and myopathological features of all patients with granulomas in muscle biopsy specimens identified over a 5-year period (1992-1996) at the Washington University Medical Center. Ten patients were found to have granulomas in their muscle biopsy specimens. Of these, eight patients had myopathic changes. Seven had dysphagia as a major functional difficulty during the course of their disease. None had elevated levels of serum creatine kinase (CK). Four of the patients with myopathy had systemic sarcoidosis and relatively severe proximal weakness with functional disability. Treatment with corticosteroids was followed by marked improvement in strength and functional disability. The four other patients with myopathy had no systemic signs of sarcoidosis. Weakness was especially prominent distally in three of these patients. The two patients in this group treated with corticosteroids did not improve. The final two patients, who had granulomas in muscle but no myopathic changes, had clinical syndromes of mononeuritis multiplex and eosinophilic fasciitis (Shulman syndrome). We conclude that granulomatous myopathy, in the presence or absence of systemic sarcoidosis, is commonly associated with dysphagia (87%) and a normal serum CK. Clinical features in patients with sarcoidosis included severe proximal weakness with functional disability that often responded to corticosteroid treatment. Granulomatous myopathy without systemic sarcoidosis was associated with milder, but more predominantly distal weakness.     

Sarcoidosis: 25-year clinical follow-up

Based on the follow-up of 1,600 patients with sarcoidosis from 1971 to 1996, the authors analyzed the value of various methods for identifying the disease, the frequency and nature of misdiagnoses. They showed the efficiency of basic treatments in patients with sarcoidosis: corticosteroidal hormones, nonhormonal antiinflammatory drugs, plasmapheresis, and physiotherapy. Recurrencies and progression were seen in 23.85% of patients. The likely causes of recurrent sarcoidosis are considered. It is concluded that recurrencies are one of the important problems of modern sarcoidosis.     

Analysis of restriction fragment length polymorphism for the HLA-DR gene in Japanese patients with sarcoidosis

BACKGROUND: It is commonly assumed that some immunological disorder may play a part in the pathogenesis of sarcoidosis. Previous studies by several groups have shown a significant association with HLA-DR antigens in patients with sarcoidosis. In this study, restriction fragment length polymorphism (RFLP) analysis of the HLA-DR gene was designed to confirm the association at the gene level and to look for a gene rearrangement which may influence susceptibility to sarcoidosis. METHODS: Thirty two unrelated Japanese patients with sarcoidosis were tested for HLA antigens and subjected to RFLP analysis after digestion with Eco RI, Pst I, Bam HI, Pvu II, and Hind III by using an HLA-DR beta cDNA probe. A group of 47 unrelated healthy Japanese subjects served as controls. Frequencies of each restriction fragment were compared between the patients and the control subjects. Correlation between fragment frequencies and clinical features were also analysed. RESULTS: No restriction fragments of HLA-DR beta gene were found specific to the patients with sarcoidosis. The RFLP analysis could detect polymorphism of HLA-DR beta genes that was not distinguishable by conventional serological methods. Several restriction fragments of the DR beta gene were seen only in DRw52 positive individuals, and showed higher frequencies in the patients than in control subjects. The patients with these DNA fragments were likely to have limited stage disease with no ophthalmic involvement. CONCLUSIONS: An association between HLA and sarcoidosis was noted at the DNA level, although no restriction fragments were specific for this disease. RFLP analysis of the HLA gene is a more useful method than the usual HLA typing, and should be the first step in identifying the gene sequence which is connected with susceptibility to sarcoidosis.     

Living situation of heart patients--long waiting list for revascularization increases uncertainty and fear]

In 80% of cases, antituberculosis antibodies from the sera of patients with tuberculosis were ascertained to react in enzyme immunoassay (EIA) with antigens (ultrasound disintegrants (USDs)) of reverse mycobacteria isolated (initially) from patients with sarcoidosis. The USDs of reverse mycobacteria isolated from patients with sarcoidosis reacted in EIA with monoclonal antibodies (MAb) against M. tuberculosis complex antigens (unique and crossover). Both common and distinctive (unique) antigenic determinants were detected via MAb against different mycobacterial types by immunoblotting in the antigenic complexes of M. tuberculosis H37Rv and reverse strains isolated from patients with sarcoidosis.     

Fluctuating currents in puncture therapy

Antibodies to Mycobacterium tuberculosis antigens H37Rv and reverse strains previously isolated from patients with sarcoidosis with granular isolates were determined in 50 patients with sarcoidosis (including 16 patients isolating granular types) and 56 patients with tuberculosis, by using ELISA and immunoblotting. Serum antibodies from patients with sarcoidosis were ascertained to more commonly react in ELISA with the antigen (ultrasound disintegrant (USDs) obtained from reverse mycobacteria isolated (initially) from patients with sarcoidosis (AGS) than with the USD of the M. tuberculosis H37Rv (AGT) and, on the contrary, serum antibodies from patients with tuberculosis more frequently reacted with the M. tuberculosis H37Rv. The spectrum of serum antibodies from patients with sarcoidosis greatly differed at immunoblotting with AGS and AGT. There was most commonly a reaction with the antigenic determinants 79, 27, 30, and 50 kDa to AGS and that of the determinants 17, 35, 32 kDa to AGT.     

The role of human leukocyte antigen in susceptibility and clinical manifestations of sarcoidosis

To investigate the association of human leukocyte antigen (HLA) with susceptibility and clinical manifestations of sarcoidosis. Fifty-five patients with sarcoidosis were studied by using allele group specific polymerase chain reaction technique (PCR). Our data show that: (1) the gene frequency of HLA-DR5 is significantly increased in patients with sarcoidosis, but that of HLA-DR7 decreased. (2) Gene frequencies of HLA-DR9 and HLA-DR5 are relatively increased in male patients and in patients with stage I and stage IIa, respectively. The results suggest that HLA-DR gene might contribute to the susceptibility as well as to the difference of clinical manifestations in sarcoidosis.     

Inducible expression of the 2-5A synthetase/RNase L system results in inhibition of vaccinia virus replication

Clinically apparent involvement of the nervous system occurs in a relatively small number of patients with sarcoidosis. The diagnosis of neurosarcoidosis is often difficult and particularly so in patients who lack either pulmonary or systemic manifestations of sarcoidosis. Furthermore, clinical features of neurosarcoidosis are extremely variable. In this series of 37 patients, seen during the last 30 years, cranial nerve palsies occurred in 52%, polyneuritis or polyneuropathy in 24%, meningeal involvement in 24%, muscle disease in 8%, and Guillain-Barré syndrome in 5% of the patients. Other presentations included seizures, brain mass, pituitary/hypothalamic syndrome, and memory loss associated with confusion. The chest radiograph was abnormal in 8 of every 10 patients with neurosarcoidosis. In 18 (85%) of 21 patients, gallium uptake was consistent with the diagnosis of active sarcoidosis. Serum angiotensin-converting enzyme levels were raised in about half of the patients. Cerebrospinal fluid features, including lymphocyte pleocytosis, raised protein levels, and decreased glucose concentration, were of little help. MRI with gadolinium enhancement was the most sensitive diagnostic tool, particularly in patients with meningeal involvement. The ultimate arbiter of the diagnosis of neurosarcoidosis, the presence of noncaseating granulomas in the involved tissue, was not always available. Although corticosteroids are the mainstay of therapy, in this series, 12 patients received chloroquine or hydroxychloroquine. Prognosis of chronic neurosarcoidosis is poor. Six (18%) of 37 patients died of complications related to sarcoidosis.     

Scanning electron microscopy of the bronchial mucosa in some lung diseases using bronchoscopy specimens. A pilot study including cases of bronchial carcinoma, sarcoidosis, silicosis and tuberculosis

In order to study the lung defence mechanisms and the mucociliary transport system scanning electron microscopy was performed on biopsy specimens obtained at bronchoscopy under local anaesthesia. There were great variations in the appearance of the cilitated epithelium from the large bronchi in 40 patients with bronchial carcinoma, sarcoidosis, silicosis, tuberculosis and other lung diseases. Areas with a low frequency of cilia were observed mainly in granulomatous disorders, and in silicosis, atypical cilia occurred abundantly. Squamous metaplasia with a complete loss of cilia was found in chronic bronchitis, bronchial carcinoma, after radiotherapy and in two of seven cases of sarcoidosis. Scanning electron microscopy seems to be an excellent method for studying the surface of the bronchial epithelium in many lung diseases, and may prove to be helpful in occupational medicine.     

Detection and quantification of protein-losing enteropathy with indium-111 transferrin

BACKGROUND: Acid fast cell wall deficient forms (CWDF) of bacteria have been grown from blood, bronchial washings, and ocular anterior chamber fluid from patients with sarcoidosis. A monoclonal antibody raised against Mycobacterium tuberculosis whole cell antigen (H37RV) was used to characterise further CWDF grown from the blood of patients with sarcoidosis. METHODS: Blood from 20 patients with active sarcoidosis and from 20 controls was cultured using methods favourable for the growth of CWDF. Isolates were further characterised by indirect fluorescent antibody analysis using a monoclonal antibody highly reactive with M tuberculosis. RESULTS: CWDF were grown from the blood of 19 of 20 subjects with sarcoidosis. All isolates stained positively with the monoclonal antibody and with a modified Kinyoun stain. No organisms were grown from the blood of controls. CONCLUSIONS: These data demonstrate that CWDF can be grown from the blood of nearly all patients with active sarcoidosis. The results confirm that the organisms are mycobacterial in origin and are similar, if not identical, to M tuberculosis. Their role in the pathogenesis of sarcoidosis is unknown.     

Therapeutic application of cytokines and future prospect of the drug design]

The biopsy of different tissues were reviewed in 34 patients with intrathoracic sarcoidosis for determining their value on the diagnosis of sarcoidosis. Biopsy of different tissues was performed by routine method. The transbronchial lung biopsy (TBLB) was done under bronchoscope. The diagnosis was confirmed in 90.9% (10/11) of the biopsies of periphery lymph nodes, 75.0% (3/4) of the scalene nodes' biopsies, 68.4% (13/19) of the transbronchial lung biopsies and 70.6% (12/17) of the bronchial mucosal biopsies (BMB) through fibroptic bronchoscopy. Only 4 in 7 patients were diagnosed through skin biopsies. Kveim test was positive in 5 of 6 patients. Both TBLB and BMB were undertaken in 16 patients. The coincidence ratio between them was as high as 81.3%. The total diagnostic percentage through bronchoscopy was 87.5%. Significant differences were found between the results of TBLB or SMB before and after 1990 (P < 0.05 and 0.01 separately proved by chi 2 test). After 1990, 85.7% of TBLBs and 92.3% of BMBs were diagnostic. According to the study, TBLB and BMB were the methods that were repeatable, highly diagnostic, less invasive, and mutually compensable. They were superior over the other methods in the diagnosis of sarcoidosis. The diagnostic yield could be elevated by the accumulation of experiences and the improvement of techniques. They deserved recommending in the clinical practice.