Association between inflammatory bowel disease and sarcoidosis. Report of two cases and review of the literature

BACKGROUND: Common etiopathogenic factors may explain the association of systemic sarcoidosis with inflammatory bowel disease. METHODS: We report two cases of such an association: one of sarcoidosis that developed 2 years after proctocolectomy for ulcerative colitis and one of sarcoidosis and Crohn's colitis. Factors like increased cellular immunity or circulating immunocomplexes or autoantibodies may have a role. Exogenous agents or familiarity may also be involved. CONCLUSIONS: It is postulated that the association between sarcoidosis and inflammatory bowel disease (both ulcerative colitis and Crohn's disease) does not occur by chance alone and that the two conditions may share some genetic or immunologic alterations. The two diseases, however, follow an independent clinical course.     

Moyamoya disease associated with pulmonary sarcoidosis--case report

A 61-year-old female presented with a unique case of moyamoya disease associated with pulmonary sarcoidosis. She was admitted for sudden onset of left temporalgia with episode of numbness on face, tongue, and upper extremity on the right side. The next morning, she had symptoms of Gerstmann syndrome and her ability to speak was disturbed. Her medical history included radical resection of lung cancer on the right side. She had no symptoms of pulmonary sarcoidosis. Neuroimaging showed an infarction in the left occipital lobe. Angiography showed occlusions of the bilateral internal carotid arteries at the supraclinoid portions. Subsequently, a left superficial temporal artery-middle cerebral artery anastomosis with encephalo-myo-synangiosis was performed. Ninety-three days after admission, she suddenly developed dyspnea which resulted in death 3 hours later. Autopsy findings showed typical epithelioid granulomas of sarcoid type in the lymph nodes of the peribronchus, lung, and liver. Thrombotic emboli were found in the bilateral pulmonary arteries, and marked fibrous intimal thickening in the bilateral internal carotid arteries. Immunological reaction with inflammatory events may cause pathological changes in patients with moyamoya disease or sarcoidosis. The co-incidence in this case suggests that some common inflammatory events may be involved in the pathogenesis of these diseases.     

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.     

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.     

Prevalence and relevance of coronary artery anomalies

A patient with scar sarcoidosis and Crohn's disease is described. The possibility of patients with Crohn's disease being more prone to develop sarcoidosis is discussed.     

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.     

Brain tumors in patients with Fanconi''s anemia

OBJECTIVES: To study whether an association between polyglandular autoimmune (PGA) syndrome type III [including autoimmune thyroid disease (ATD) and insulin-dependent diabetes mellitus (IDDM)], coeliac disease and sarcoidosis, exists. DESIGN: In patients with documented sarcoidosis, the presence of the disease constellation of ATD, IDDM and coeliac disease was examined. SETTING: The patients were recruited at the Department of Pulmonary Medicine, and the study was conducted at the Department of Endocrinology, Lund University Clinics, General Hospital, Malm?, Sweden. SUBJECTS: Of all patients (n = 89) with documented sarcoidosis attending the Department of Pulmonary Medicine between January 1980 and December 1991, 78 patients (44 males, 34 females: median age at the time of the study 48 years, range 22-81 years: median observation time since the diagnosis of sarcoidosis 120 months, range 1-468 months) were examined in the present study. RESULTS: Amongst the 78 patients with documented sarcoidosis, one female patient was found with PGA syndrome type III, coeliac disease and sarcoidosis. CONCLUSIONS: This present patient further indicates the existence of an association between polyglandular autoimmune (PGA) syndrome type III, coeliac disease and sarcoidosis. To determine whether this disease constellation might constitute a new syndrome, further studies on larger groups of patients with sarcoidosis are demanded.     

Systemic cyclosporine and low-dose prednisone in the treatment of chronic severe alopecia areata: a clinical and immunopathologic evaluation

We report a case of interstitial lung disease developing during treatment with chlorambucil, vinblastine, procarbazine and prednisone for extrapulmonary Hodgkin's disease. Transbronchial biopsies demonstrated noncaseating epithelioid cell granulomata, and bronchoalveolar lavage fluid showed an increased percentage of lymphocytes, with a raised T cell helper-suppressor ratio, suggesting a diagnosis of sarcoidosis. Treatment with corticosteroids brought about complete resolution of the radiographic lesions. A possible relationship between sarcoidosis and lymphoma is discussed, and a short review of the literature is given. This case report has some unique features that, to our knowledge, have not been published before.     

Lung transplantation for pulmonary sarcoidosis

Patients with end-stage sarcoidosis have now undergone lung transplantation successfully with good short-term and intermediate-term results. Lung transplantation for sarcoidosis requires several considerations unique to this disease. Selection of pulmonary sarcoidosis patients for transplantation requires that medical therapy has been exhausted. This may involve the use of corticosteriods and alternative medications. Causes of pulmonary dysfunction other than pulmonary sarcoidosis, such as bronchiectasis and myocardial sarcoidosis, must be excluded before candidates are considered for transplantation. The extent and severity of extrapulmonary disease must also be assessed and may preclude lung transplantation. The presence of mycetomas is considered a relative contra-indication by some transplant centres and an absolute contra-indication by others. Relatively few patients with pulmonary sarcoidosis have undergone transplantation and, therefore, there are few data on outcome. Sarcoidosis frequently recurs in the allograft, but rarely causes symptoms or pulmonary dysfunction. More severe acute rejection episodes may occur in sarcoidosis transplant recipients, although at present there is no evidence of an increased risk of obliterative bronchiolitis or increased mortality.     

"The sarcoidosis map": a joint survey of clinical and immunogenetic findings in two European countries

We pooled immunogenetic data obtained in independent studies in two European populations (Italian and Czech) of patients affected by sarcoidosis. Correspondence analysis was used to investigate the associations between clinical and immunogenetic data. Two hundred and thirty-three patients were enrolled in the study, of which 126 were from the Czech Republic and 107 from Italy. Using a common protocol, we examined each patient for sex, age of disease onset, roentgenologic stage, extrapulmonary spread, and clinical course. One thousand and ten healthy individuals, HLA typed for class I and II serologic polymorphisms, served as controls. Findings that were essentially in agreement in both populations were: (1) a positive association of sarcoidosis with HLA-A1, B8, and DR3 markers, and a negative association with HLA-B12 and DR4; (2) a prevalence of HLA-DR3 and DR4 among females and of DR5 among males; (3) a relationship of B13 and B35 with early onset and of A30, B8, DR3, and DR4 with late onset of disease; (4) an association of B27 with sarcoidosis restricted to the lungs; (5) a relationship of A1, B8, B27, and DR3 to roentgenologic stage I and of B12 and DR4 to stage III; and (6) an association of HLA-DR3 with a good outcome. Population-restricted findings essentially concerned the alleles HLA-B13 and B22, the former being associated with the disease, male sex, early onset, extrapulmonary localization and relapse only in Czechs, and the latter to disease spread only in Italians. Our results seem to support the concept that immunogenetic background may at least partly account for the clinical heterogeneity of sarcoidosis.     

Nuclear imaging. 67Gallium, 201thallium, 18F-labeled fluoro-2-deoxy-D-glucose positron emission tomography

67Gallium scan has been used for years in sarcoidosis as a marker of activity, a determiner of the extent and distribution of the disease, a diagnostic support, and an aid in therapeutic management. Because of its limited sensitivity and specificity for sarcoidosis, however, it is currently used mainly to assist in diagnosis in difficult cases, particularly in those with isolated extrathoracic sarcoidosis. The finding of the typical lambda or panda patterns supports the diagnosis and reinforces the indication to perform an appropriate biopsy or Kveim-Siltzbach test. In addition, the detection of clinically silent extrathoracic uptake may provide sites for biopsy. 67Gallium scans' routine use in the follow-up of pulmonary sarcoidosis under treatment has decreased because that is best accomplished by means of serial chest radiographs and PFT. 201Thallium scintigraphy studies the myocardial perfusion and is complementary to echocardiography and 24-hour electrocardiographic monitoring in the assessment of sarcoid cardiac involvement. It typically shows segmental areas of decreased uptake in the ventricular myocardium that disappear or decrease in size during stress or after intravenous administration of dipyridamole. That reverse distribution is not specific for cardiac sarcoidosis, however, because it may also occur in other cardiomyopathies. PET is based on the increase of glucose metabolism in inflamed tissues. It may have great potential to assess sarcoidosis activity, but it is still largely experimental and is not routinely employed.     

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.     

Intermittent azoospermia associated with epididymal sarcoidosis

OBJECTIVE: To report an unusual case of intermittent azoospermia associated with epididymal sarcoidosis. DESIGN: Retrospective case analysis. SETTING: Wilford Hall Medical Center. PATIENT(S): A 36-year-old male with secondary infertility and epididymal sarcoidosis. INTERVENTION(S): None. MAIN OUTCOME MEASURES(S): An analysis of sperm count in relation to steroid courses. RESULTS(S): Epididymalgia, and to a lesser extent, sperm counts were noted to fluctuate temporally around steroid courses given for pulmonary flares of sarcoidosis. Epididymal sarcoidosis can be associated with intermittent azoospermia. Presumably, epididymal granulomas undergo exacerbations and remissions and cause intermittent ductal obstruction. CONCLUSIONS(S): Because of the unpredictable effect of sarcoidosis on the male genital tract, all patients interested in paternity should obtain a semen analysis at the time of disease diagnosis. If oligospermia is noted or if there is clinical evidence of epididymal involvement, the patient should be offered sperm banking for possible future assisted reproductive techniques.     

Inhibition of nitric oxide synthesis increases adenosine production via an extracellular pathway through activation of protein kinase C

At the time of diagnosis, many sarcoidosis patients have no clinical indication for corticosteroid therapy, and prognostic parameters predicting deterioration are missing. In the present study, we investigated parameters derived from bronchoalveolar lavage (BAL) and serum in 77 patients with recently diagnosed sarcoidosis to test their predictive value. Patients were divided into a group with (Group A, n = 37) and a group without (Group B, n = 40) indications for therapy, and the course of the disease was evaluated after 5.7 +/- 0.4 mo. The CD4+/CD8+ lymphocyte ratio and percentage of BAL lymphocytes were of no predictive value. Release of tumor necrosis factor-alpha (TNF-alpha) from cultured alveolar macrophages (AM) was significantly increased in both groups (Group A = 1,872 +/- 428 pg/ml; Group B = 1,561 +/- 449 pg/ml) as compared with controls (220 +/- 37 pg/ml). In Group B, however, patients with a high level of TNF-alpha release had a significantly greater risk of disease progression than did those with normal TNF-alpha release (43.8% versus 8.3%, respectively). From the serologic parameters investigated, consisting of neopterin, angiotensin converting enzyme (ACE), and soluble interleukin-2 receptor (sIL-2R), only the last was of significant predictive value; 42.1% of sarcoidosis patients in Group B with a high level of sIL-2R experienced disease progression, whereas none of those with a normal level did. We conclude that TNF-alpha release and sIL-2R are suitable parameters for predicting disease progression in sarcoid patients who have no indication for therapy at the time of disease diagnosis.     

Possible transmission of sarcoidosis via allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) was performed in a 34-year-old man for non-Hodgkin's lymphoma. Two years before bone marrow harvest, pulmonary sarcoidosis was diagnosed in the donor. After steroid therapy, disease of the donor was in clinical remission with only minor radiological signs at the time of BMT. On day 90 after BMT, active sarcoidosis was diagnosed in the recipient. Besides radiologic signs and increased angiotensin converting enzyme levels, diagnosis was proved by characteristic histologic changes in lung and liver biopsies. Immunosuppressive therapy was changed from high dose cyclosporine to high dose methylprednisolone and symptoms promptly resolved within 10 weeks. This case indicates the possibility of transmission of sarcoidosis by marrow transplantation.     

Sarcoidosis: a pediatric perspective

Childhood sarcoidosis is a rare multisystemic granulomatous disease of unknown etiology. The clinical presentation can vary greatly depending upon the organs involved. Two distinct forms of sarcoidosis exist in children. Older children usually present with a multisystem disease similar to the adult manifestation, with frequent hilar lymphadenopathy and pulmonary infiltration. Early-onset childhood sarcoidosis is a unique form of the disease characterized by the triad of rash, uveitis, and arthritis in patients presenting before age 4 years. The diagnosis of sarcoidosis is confirmed by demonstrating a typical noncaseating granuloma on a biopsy specimen. The current therapy of choice for childhood sarcoidosis with multisystem involvement is corticosteroids. Methotrexate given orally in low doses is effective and safe and has steroid-sparing properties.     

Noninvasive assessment of the direct action of oral nifedipine and nicardipine on left ventricular contractile state in patients with systemic hypertension: importance of reflex sympathetic responses

BACKGROUND: Alveolar macrophages from patients with sarcoidosis were analyzed for their ability to secrete tumor necrosis factor-alpha (TNF-alpha), interleukin-1-beta (IL-1-beta), and interleukin-6 (IL-6). RESULTS: Constitutive release of all three monokines in these patients was concomitantly increased in the active state of disease in comparison with inactive sarcoidosis or healthy control subjects. Alveolar macrophages from patients with inactive sarcoidosis compared with cells from healthy subjects showed increased spontaneous secretion of TNF-alpha and IL-6 only, whereas the constitutive release of IL-1-beta was similar as in healthy volunteers. In vitro stimulation of alveolar macrophages from healthy control subjects with lipopolysaccharide or pokeweed mitogen led to a time- and dose-dependent enhanced secretion of TNF-alpha, IL-1-beta, and IL-6. In a similar manner, with corresponding cells from patients with sarcoidosis the secretion of all three cytokines could be further increased by stimulation with lipopolysaccharide or pokeweed mitogen. CONCLUSIONS: The data presented indicate that an increased release of TNF-alpha, IL-1-beta, and IL-6 correlates to disease activity and may play a critical part in the pathogenesis of sarcoidosis.     

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.     

Non-Hodgkin's lymphoma in a patient with sarcoidosis (the sarcoidosis-lymphoma syndrome)]

A-31-year-old man with right cervical and supraclavicular lymphadenopathy was admitted in March, 1991. He was diagnosed as having muscular sarcoidosis at the age 8 year, and was treated with corticosteroids. Since age 18, his skin was erythematous and ulcerous, and later his skin became gradually atrophic. Lymph node biopsy revealed diffused large cell non-Hodgkin's lymphoma. Lymphoma cells showed TCR-beta gene rearrangement by Southern blot hybridization. His lymphoma was refractory to CHOP and CHOP-Bleo regimens. Complete remission was achieved with cisplatin and etoposide. However, early relapse occurred, and he died of pulmonary hemorrhage 4 months after the diagnosis of non-Hodgkin's T-cell lymphoma. The so called "sarcoidosis-lymphoma syndrome" is uncommon in Japan. In 9 of 10 cases previously reported, malignant lymphoma occurred during the course of sarcoidosis. Most of the sarcoidosis cases were chronic active type, and required systemic administration of corticosteroids. Hodgkin's disease coexistent with sarcoidosis as reported in other countries, was not found in Japan. These findings suggest that the low incidence of sarcoidosis-lymphoma syndrome in our country is due to the relative rareness of Hodgkin's disease. The sarcoidosis-lymphoma syndrome possibly appears as a consequence of immunological abnormalities observed in sarcoidosis.