Spontaneous Remission Of Disease Research Articles

Autoimmune Neutropenia of Infancy Is Almost Exclusively Caused By IgG Antibodies

Background The relevance of IgM antibodies in autoimmune mediated hemocytopenias remains a matter of debate. For autoimmune neutropenia, conflicting results were published. This study was performed as part of the Giessen Neutropenia Registry, which prospectively included children with suspected autoimmune neutropenia. Methods Children with suspected autoimmune neutropenia were prospectively enrolled and data central to their suspected diagnosis were collected over 3 years. Sera were tested for the presence of autoantibodies against neutrophils by granulocyte immunofluorescence test (GIFT) and granulocyte agglutination test (GAT). The presence of IgG and IgM antibodies was assessed in a subgroup of patients with positive initial GIFT in whom spontaneous remission of their neutropenia was documented. Results A total of 406 children were included in the study. A remission was reported for 114 patients during the study period. Of those, 96 children (84%) had an initial positive GIFT. Their median age at diagnosis was 11 months (7-17.5), and their mean neutrophil count was 293 (±267)/µL, ranging from 0 to 975. In total 75/96 (78%) of children had at least one documented infection at diagnosis. In 29/96 (30%), a bone marrow aspirate was available. At the documented time point of remission, children were 27 months (18-41) old. In the initial sample send for diagnosis, IgG antibodies against neutrophils were detected in 94/96 children (98%), and IgM antibodies were detected in 2/96 (2%). We did not observe children with autoantibodies of both Ig classes. Conclusion To our knowledge, this is the first study to demonstrate the contribution of IgG or IgM antibodies in a well-defined clinical cohort with a typical course including, spontaneous disease remission. IgG antibodies were present in 98%. Only very rarely, IgM antibodies can be detected. We conclude that in general, screening for IgG autoantibodies is appropriate as a first diagnostic step. In cases with strong clinical suspicion but negative GIFT with anti-IgG, anti-IgM testing may be considered.

Sarcoidosis: Updates on therapeutic drug trials and novel treatment approaches.

Sarcoidosis is a systemic granulomatous inflammatory disease of unknown etiology. It affects the lungs in over 90% of patients yet extra-pulmonary and multi-organ involvement is common. Spontaneous remission of disease occurs commonly, nonetheless, over 50% of patients will require treatment and up to 30% of patients will develop a chronic progressive non-remitting disease with marked pulmonary fibrosis leading to significant morbidity and death. Guidelines outlining an immunosuppressive treatment approach to sarcoidosis were recently published, however, the strength of evidence behind many of the guideline recommended drugs is weak. None of the drugs currently used for the treatment of sarcoidosis have been rigorously studied and prescription of these drugs is often based on off-label” indications informed by experience with other diseases. Indeed, only two medications [prednisone and repository corticotropin (RCI) injection] currently used in the treatment of sarcoidosis are approved by the United States Food and Drug Administration. This situation results in significant reimbursement challenges especially for the more advanced (and often more effective) drugs that are favored for severe and refractory forms of disease causing an over-reliance on corticosteroids known to be associated with significant dose and duration dependent toxicities. This past decade has seen a renewed interest in developing new drugs and exploring novel therapeutic pathways for the treatment of sarcoidosis. Several of these trials are active randomized controlled trials (RCTs) designed to recruit relatively large numbers of patients with a goal to determine the safety, efficacy, and tolerability of these new molecules and therapeutic approaches. While it is an exciting time, it is also necessary to exercise caution. Resources including research dollars and most importantly, patient populations available for trials are limited and thus necessitate that several of the challenges facing drug trials and drug development in sarcoidosis are addressed. This will ensure that currently available resources are judiciously utilized. Our paper reviews the ongoing and anticipated drug trials in sarcoidosis and addresses the challenges facing these and future trials. We also review several recently completed trials and draw lessons that should be applied in future.

Non-invasive monitoring of arthritis treatment response via targeting of tyrosine-phosphorylated annexin A2 in chondrocytes

BackgroundThe development and optimization of therapies for rheumatoid arthritis (RA) is currently hindered by a lack of methods for early non-invasive monitoring of treatment response. Annexin A2, an inflammation-associated protein whose presence and phosphorylation levels are upregulated in RA, represents a potential molecular target for tracking RA treatment response.MethodsLS301, a near-infrared dye-peptide conjugate that selectively targets tyrosine 23-phosphorylated annexin A2 (pANXA2), was evaluated for its utility in monitoring disease progression, remission, and early response to drug treatment in mouse models of RA by fluorescence imaging. The intraarticular distribution and localization of LS301 relative to pANXA2 was determined by histological and immunohistochemical methods.ResultsIn mouse models of spontaneous and serum transfer-induced inflammatory arthritis, intravenously administered LS301 showed selective accumulation in regions of joint pathology including paws, ankles, and knees with positive correlation between fluorescent signal and disease severity by clinical scoring. Whole-body near-infrared imaging with LS301 allowed tracking of spontaneous disease remission and the therapeutic response after dexamethasone treatment. Histological analysis showed preferential accumulation of LS301 within the chondrocytes and articular cartilage in arthritic mice, and colocalization was observed between LS301 and pANXA2 in the joint tissue.ConclusionsWe demonstrate that fluorescence imaging with LS301 can be used to monitor the progression, remission, and early response to drug treatment in mouse models of RA. Given the ease of detecting LS301 with portable optical imaging devices, the agent may become a useful early treatment response reporter for arthritis diagnosis and drug evaluation.

Narcolepsy Type 1: A Remitting Disease? An Unusual Case Report

We describe the case of a male patient who was diagnosed with narcolepsy type 1 on the basis of sleep and wake symptoms, and the results of investigations including video-polysomnography, multiple sleep latency test, human leukocyte antigen status and orexin level in cerebrospinal fluid. During the first years after disease onset, the patient did not show any significant improvement despite treatment with a variety of stimulant and anti-cataplectic drugs. However, spontaneous remission of disease occurred after 15 years.

SUN-383 Sustained Clinical Improvement after Discontinuation of Mifepristone: Unexpected Remission of Hypercortisolism

Background: The competitive GR antagonist mifepristone (MIFE, Korlym®, Corcept Therapeutics) has been used in the treatment of patients with hypercortisolism of unknown origin. In most patients, symptoms (e.g., hyperglycemia, weight gain, or psychiatric symptoms) return within several weeks if MIFE is discontinued in patients whose symptoms have improved. Here we describe a case of a patient who experienced clinical improvement in symptoms attributed to her excess cortisol for 4+ months after discontinuation of MIFE. Case Presentation: A 39-year-old woman presented with a history of significant increase in weight as well as hyperglycemia, migraines, poor sleep, and fatigue. Onset of conditions occurred 3 years prior when pt was diagnosed with thyroid cancer, which was treated with total thyroidectomy and iodine ablation leading to hypothyroidism. Despite being euthyroid and in cancer remission, her comorbidities did not improve. Before cancer diagnosis, patient’s weight was 160 lbs (BMI 26.6), but, after cancer diagnosis, increased to a max of 210 lbs (BMI 34.9), despite strenuous exercise and modifications to diet. Phentermine (phen) (37.5 mg) was prescribed daily, but pt lost only 8 lbs in 2 months. With unsuccessful attempts at weight loss, history of psychological stress due to cancer diagnosis, fatigue, poor sleep, and hypokalemia possibly attributed to mineralcorticoid receptor activation, hypercortisolism was suspected. Dexamethasone suppression test (DST) 1 mg revealed cortisol level of 2.6 µg/dL. Because of the unknown origin of hypercortisolism (the patient refused imaging), MIFE 300 mg QD and spironolactone 25 mg QD (for hypokalemia) were initiated. Lower limb edema and hypokalemia were observed at 4 months, and both were corrected by restarting spironolactone and with potassium supplementation. At month 6, weight had decreased 37 lbs, and fasting blood glucose (FBG) decreased from 118 to 89 mg/dL. Sleep quality and fatigue improved, and migraines ceased. After weight and FBG normalized, MIFE was stopped at month 6 to repeat DST. Unexpectedly, a repeat DST was normal at 0.4 µg/dL. Clinical benefit has been maintained for 4+ months. Pituitary and adrenal imaging was ordered again but pt refused citing that her life has improved dramatically and that she didn’t want any more testing for now. Conclusion: Four months after discontinuation of MIFE, hypercortisolism, obesity, migraines, poor sleep, and hyperglycemia remain resolved. We hypothesize that the patient’s sustained clinical improvements could be the result of an HPA axis reset, decreased stress, and/or spontaneous remission of disease.

IVIG efficacy in CIDP patients is not associated with terminal complement inhibition

Patients with acute and chronic inflammatory demyelinating neuropathies exhibit elevated serum and cerebrospinal fluid (CSF) levels of terminal complement activation products and therapeutic inhibition of complement activation is currently tested for its safety and efficacy in patients with Guillain-Barré syndrome (GBS). Here, we determined serum levels of the complement activation products C3a, C5a and the soluble terminal complement complex (sTCC) in 39 individuals with chronic inflammatory demyelinating polyneuropathy (CIDP) who participated in one of the largest ever conducted clinical trial in patients with CIDP (ICE trial) and received Intravenous Immunoglobulin (IVIG) or placebo (albumin) in 3 week intervals for up to 24 weeks. In placebo-treated patients with spontaneous disease remission, serum sTCC levels moderately decreased over time. Levels of complement activation products were, however, not modulated by IVIG and remained unchanged in patients with a beneficial response to IVIG therapy as compared to those with steady or worsened disease. These results suggest that the therapeutic efficacy of IVIG in CIDP is based on immunomodulatory mechanisms different from complement inhibition. Terminal complement activation merits further investigation as a surrogate marker for disease progression and therapeutic target in patients with CIDP.

Chronic urticaria - What does the new guideline tell us?

Patients with chronic urticaria experience significant impairment, and require an effective treatment. Such treatment is preceded by a thorough diagnostic workup and measurement of disease activity, disease burden and disease control using well--established tools. Treatment is subsequently adjusted according to patient needs and therapeutic response, based on the tenet "as much as necessary, as little as possible" (in that order). Once disease control has been achieved, it is recommended that intermittent attempts at medication withdrawal be made in order to identify spontaneous disease remission. Chronic urticaria should be treated until spontaneous remission occurs.

Predictive values of different forms of human chorionic gonadotropin in postmolar gestational trophoblastic neoplasia.

The aim of this study was to reach a publicly applicable marker, using the increasing or decreasing trend of different forms of β-human chorionic gonadotropin (β-hCG) during the first 28 days after molar pregnancy evacuation. The present retrospective cohort study investigated all of the documents of patients with hydatidiform mole according to their pathological results during their admission and follow-up in the past 10 years (2003-2013). The type of the relationship was determined using locally weighted scatterplot smoothing (Lowess Smoother) and fractional polynomial regression (Fracpoly), and then a model tailored to data processing was used for drawing the receiver operating characteristic curve. During the investigation of gestational trophoblastic neoplasia (GTN) risk factors, the multiple logistic regression method was used to control the confounding variables. Among individuals with high-risk molar pregnancy, 11 (18%) had GTN, and the prevalence of GTN in individuals with low-risk molar pregnancy was 13.4%. The slope of the β-hCG line slightly decreases with a rate of change close to zero in individuals with GTN, but the decrease is not statistically significant (P > 0.05). The receiver operating characteristics curve for serum β-hCG measurement after 21 days of molar pregnancy evacuation showed 83% sensitivity at 89% specificity (area under the curve, 0.9), which indicates that this variable has an optimal performance for discrimination between the GTN cases and patients who had spontaneous disease remission. The mean times of reaching the first negative titer in those without neoplasia and reaching a definitive GTN diagnosis were 8.1 (SD, 2) and 6.2 (SD, 1.5), respectively. The most effective remaining variable in the logistic model was uterine size larger than gestational age (95% confidence interval, 0.99-1.31; odds ratio, 1.14) with a slight increase in the risk and borderline significance (P = 0.07). The serum β-hCG measurement after 21 days of molar pregnancy evacuation and slope of the linear regression line of β-hCG showed to be a good test to discriminate between patients who will get spontaneous disease remission and patients developing GTN.

The Emergence of Wellbeing in Community Participation

This paper explores and reflects upon the literature and several mini case studies to recommend a change of focus for the linking management and development of community participants and community organisations. This change of focus looks at complexity and patterns that arise from the multitude of social interactions; the support and development of individuals and the effect this can have on an organisation’s wellbeing; and the effect a community organisation can have on that of the individual. To gain insight into wellbeing, people need to be aware of their mind, body and energy and how they affect others. There is evidence that terminally ill people who have found new beliefs have experienced a spontaneous remission of disease. Humanity evolves in the same way as we control our destiny. We can learn to love, respect, trust, and commit to each other and work in harmony, or we can foster disharmony resulting in failure and negative feelings. As the economy changes, community organisations are under threat of extinction. Just as species and humanity evolve, we suggest that community organisations need to evolve to ensure wellbeing.

Linear Regression of Postevacuation Serum Human Chorionic Gonadotropin Concentrations Predicts Postmolar Gestational Trophoblastic Neoplasia

Currently, human chorionic gonadotropin (hCG) follow-up after evacuation of hydatidiform moles is essential to identify patients requiring chemotherapeutic treatment for gestational trophoblastic neoplasia (GTN). We propose a model based on linear regression of postevacuation serum hCG concentrations for the prediction of GTN. One hundred thirteen patients with at least 3 serum samples from days 7 to 28 after evacuation were selected from the Dutch Central Registry for Hydatidiform Moles (1994-2009). The slopes of the linear regression lines of the first 3 log-transformed serum hCG and free β-hCG values were calculated. Receiver operating characteristic curves were constructed to calculate areas under curve (AUCs). The slope of the hCG regression line showed an AUC of 0.906 (95% confidence interval, 0.845-0.967). Gestational trophoblastic neoplasia could be predicted in 52% of patients with GTN at 97.5% specificity (cutoff, -0.020). Twenty-one percent of patients with GTN could be predicted before diagnosis according to the International Federation of Gynecology and Obstetrics 2000 criteria. The slope of free β-hCG showed an AUC of 0.844 (95% confidence interval, 0.752-0.935), 69% sensitivity at 97.5% specificity, and 38% of patients with GTN could be predicted before diagnosis according to the International Federation of Gynecology and Obstetrics criteria. The slope of the linear regression line of hCG proved to be a good test to discriminate between patients who will achieve spontaneous disease remission and patients developing GTN. The slope of free β-hCG seems to be a better predictor for GTN than the slope of hCG. Although this model needs further validation for different assays, it seems a promising way to predict the more aggressive cases of GTN.

Response Rate of 16% and High Incidence of Adverse Events In Placebo-Treated Patients with CD25 Assay-Positive Cutaneous T-Cell Lymphoma (CTCL): An Analysis of Patient Characteristics and Predictors of Response

AbstractAbstract 4158 Background:CTCLs are rare, extranodal non-Hodgkin's lymphomas characterized by the accumulation of malignant T lymphocytes in the skin; mycosis fungoides (MF) and Sézary syndrome (SS) are the most common variants. Their clinical course is typically chronic and progressive, despite multiple therapeutic interventions. Observational studies of patients with CTCL, although limited by rarity, are necessary to improve understanding of prognostic factors. Aims:The goals of this analysis were to describe the initial disease characteristics, prognostic factors, and natural history of disease observed in 44 patients with CD25-positive, recurrent/persistent CTCL included in the placebo arm of Study L4389-11. We were particularly interested to determine if there were any characteristics peculiar to the 16% of patients treated with placebo who were observed to have a response in this study. Methods:This multicenter, randomized, double-blind, placebo-controlled phase III trial compared 2 different doses of denileukin diftitox (9 or 18 μ g/kg/day) with placebo in 144 patients with histopathologically confirmed stage IA to III MF/SS who had received ≤3 previous therapies. Medications essential for patient welfare (cardiac medications, narcotics, anti-nausea agents, vitamins, or laxatives) and transfusions were also allowed. The primary efficacy endpoint was overall response rate (ORR); progression-free survival (PFS) was a secondary endpoint. Relationships between baseline covariates and clinical outcomes were assessed by multivariate regression analyses. Results:Placebo-treated patients had a median age of 59.0 years, and the majority were white (77.3%), had early-stage disease (stage <IIA; 68.2%), had a diagnosis of MF (84.1%), and had <20% circulating abnormal lymphocytes (85.4%) at baseline. The ORR was 15.9% (95% exact confidence interval [CI]: 6.6%-30.1%) for patients receiving placebo (complete response: 2.3%; partial response: 13.6%), reflecting a possible baseline rate of spontaneous disease remission expected in untreated CTCL. Of the 7 responding patients, 3 were treated during the trial with systemic anti-staphylococcal antibiotics (2 pts with IIB, 1pt with erythroderma). Of the remaining 4 pts the stages were 1A (1), IB (2), IIB (1). Median PFS according to Kaplan-Meier analysis was 124 days (4.1 months) (95% exact CI: 92–176 days (3.0-5.8 months)), and the median values for patients with stage ≤IIA disease and stage ≥IIB disease at baseline were 107 days (3.5 months) and 211 days (6.9 months), respectively. Multivariate analyses identified no significant effects of any baseline factors on either ORR or PFS, although there was a trend toward poorer PFS associated with advanced age (hazard ratio: 1.21; 95% CI: 0.97–1.52; P=.0947). These analyses were likely limited by small sample size. A total of 95.5% of patients in the placebo arm used rescue medications (skin moisturizers etc.) at least once during the treatment period. Adverse events (AEs) and treatment-related AEs occurred in 90.9% and 59.1% of placebo-treated patients, respectively. General disorders and administration site conditions were the most common types of treatment-related AEs (52.3%), which included fatigue (22.7%), rigors (15.9%), peripheral edema (15.9%), pyrexia (13.6%), and pain (2.3%). Sepsis occurred significantly more often with placebo versus active treatment (6.8% vs. 0%; P < .05). Three of the 7 (43%) responders had received systemic antibiotics and 14/37 non-responders had received systemic antibiotics (38%). Conclusion:The findings from this study demonstrate that responses can be observed in patients with MF/SS in the absence of anti-tumor treatment. Likely contributing factors to these ‘spontaneous responses’ are the use of systemic antibiotics, aggressive ‘rescue medication’ use and the waxing and waning nature of skin lesions, particularly in early-stage disease. All future studies should carefully document the use of systemic antibiotics during therapy. These results can serve as standard comparators for other active-treatment studies that lack a placebo control arm. Disclosures:Prince:Eisai: Consultancy, Honoraria. Duvic:Eisai: Consultancy, Research Funding, Speakers Bureau. Assaf:Eisai: Consultancy, Honoraria. Straus:Eisai: Consultancy, Honoraria.

Prevalence of clinical remission in patients with sporadic idiopathic hypoparathyroidism

Remission of disease activity is a characteristic feature of autoimmune endocrine disorders such as Graves' disease, Addison's disease and occasionally in patients with premature ovarian failure. Autoimmunity is also implicated in sporadic idiopathic hypoparathyroidism (SIH) with clinical remission of disease reported in three cases. To assess the rate of remission in patients with sporadic idiopathic hypoparathyroidism and review the cases reported so far. Subjects included 53 patients (M:F, 24:29) with SIH who had been symptomatic for at least 1 year (range 1-31 years). They were treated with calcium and 1-alpha-(OH)D(3)/cholecalciferol therapy and had a mean duration of follow up of 5.0 +/- 3.2 years. Treatment was withdrawn in two stages in the patients who maintained normal levels of serum total calcium during the preceding year of treatment. In stage-1, the dose of therapy was reduced to half and subsequently all treatment was stopped (stage 2) in those patients who maintained normal serum total calcium levels on the reduced dose. Remission of SIH was defined as maintenance of normal serum total (>or=2.12 mmol/l) and ionized calcium, inorganic phosphorus and serum intact parathyroid hormone (iPTH) for at least 3 months after withdrawal of calcium and 1-alpha-(OH)D(3)/cholecalciferol therapy. Calcium sensing receptor autoantibodies (CaSRAb) were determined by Western blot. Two of the 53 patients (3.8%) with SIH stayed in remission for 1 year after complete withdrawal of therapy. CaSRAb was absent in both the cases. The clinical features, age at onset and duration of hypocalcaemic symptoms in cases with remission were comparable to those who did no show remission. Sporadic idiopathic hypoparathyroidism is not irreversible as is widely believed and spontaneous remission of disease may occur in 3.8% of patients.

Regulatory T cells in the control of inflammatory demyelinating diseases of the central nervous system

New concepts in fundamental immunology, in particular the identification of a lineage of CD4 T cells endowed with regulatory properties, have revolutionized the understanding of immune-mediated diseases both in experimental models and in humans. The impact of the T regulatory cells, characterized by the expression of CD25 and the foxp3 transcription factor, on the development and remission from central nervous system inflammation, and their therapeutic potential, is being aggressively studied in preclinical animal models. Recent data indicate that the CD4CD25foxp3 T regulatory cells act both at the level of secondary lymphoid organs and in the inflamed central nervous system during experimental autoimmune encephalomyelitis. They contribute to the natural protection against autoimmunity and participate in the spontaneous remission of disease. Their role in multiple sclerosis is still unclear, but convergent data indicate that circulating CD4CD25 T cells from patients with multiple sclerosis exhibit defective regulatory properties. Several disease-modifying therapies act on T regulatory cells and their beneficial effects on multiple sclerosis could, in part, result from this mode of action. A better understanding of the induction of T regulatory cells, of their mechanisms of action, and of approaches to manipulate them in vivo may offer new therapeutic opportunities for patients with multiple sclerosis.

Paradoxical effects of tumour necrosis factor-α in adjuvant-induced arthritis

Anti-tumour necrosis factor (TNF)α therapy is highly effective in rheumatoid arthritis and it is surprising, therefore, that a recent study showed that intraperitoneal administration of recombinant TNFα reduced the severity of adjuvant-induced arthritis and decreased IFNγ expression in cultured draining lymph node cells. Furthermore, in untreated arthritic rats, maximal TNFα expression in draining lymph node cells coincided with spontaneous disease remission, suggesting a role for endogenous TNFα in recovery from arthritis. If confirmed in further studies, these findings suggest that, in addition to its well-established pro-inflammatory properties, TNFα may also play a disease-limiting role in this model of rheumatoid arthritis by suppressing effector T cell responses.

Correlation of plasma monocyte chemoattractant protein-1 (MCP-1) and monocyte inflammatory protein-1alpha (MIP-1alpha) levels with disease activity and clinical course of sarcoidosis.

MCP-1 and MIP-1alpha exhibit chemotactic activity toward macrophages/monocytes and induce the production of inflammatory cytokines affecting granuloma formation. Up-regulated expression of MCP-1 and MIP-1alpha in the affected organ of sarcoidosis has been shown; however, the relationship between their plasma levels and the clinical course of this disease has not been determined. In the present study we measured plasma MCP-1 and MIP-1alpha levels in 26 patients with active sarcoidosis by ELISA in order to assess the state of MCP-1 and MIP-1alpha in this disease. Most patients in this study (21/26) had clinical evidence of extrathoracic disease in addition to pulmonary involvement. In addition, a high proportion of patients (n = 15) showed spontaneous remission of disease, whereas five patients showed no spontaneous remission and six patients were treated with corticosteroids over the 2-year period of study. At the time of diagnosis, both plasma MCP-1 and MIP-1alpha levels in patients with active sarcoidosis were significantly higher than in the normal controls. The levels of these cytokines in patients with extrathoracic disease were compatible with those in patients without extrathoracic disease. A longitudinal evaluation of plasma MCP-1 and MIP-1alpha levels showed that the changes in both cytokines were closely related to the clinical course of sarcoidosis. These results suggest that plasma MCP-1 and MIP-1alpha may be useful parameters for monitoring the clinical course of sarcoidosis. In addition, plasma MCP-1 and MIP-1alpha may reflect subclinical evidence of extrathoracic sarcoidosis and may play a role in initiating monocyte migration into the tissue.

Fas-mediated apoptosis in clinical remissions of relapsing experimental autoimmune encephalomyelitis.

PLP139-51-induced experimental autoimmune encephalomyelitis (R-EAE) displays a relapsing-remitting paralytic course in female SJL mice. We investigated the role of apoptosis/activation-induced cell death (AICD) in the spontaneous recovery from acute disease. Clinical EAE was significantly enhanced in Fas (CD95/APO-1)-deficient SJL lpr/lpr mice, which displayed significantly increased mean peak clinical scores, reduced remission rates, and increased mortality when compared with their SJL +/lpr littermates. PLP139-151-specific proliferative responses were fairly equivalent in the 2 groups, but draining lymph node T cells from SJL lpr/lpr mice produced dramatically increased levels of IFN-gamma. Central nervous system (CNS) Fas and FasL mRNA levels in wild-type SJL (H-2(s)) mice peaked just before spontaneous disease remission and gradually declined as disease remitted. We applied the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay to detect apoptosis in situ in spinal cords of mice at various clinical stages of EAE. Most TUNEL(+) cells were found during active periods of inflammation: the acute, peak, and relapse time points. Significantly fewer apoptotic cells were observed at preclinical and remission time points. Collectively, these findings indicate that Fas-mediated apoptosis/AICD plays a major role in the spontaneous remission after the initial acute inflammatory episode and represents an important intrinsic mechanism in regulation of autoimmune responses.

Sarcoidosis

Sarcoidosis is an idiopathic granulomatous disease involving one or more multiple organ systems, characterized by the histologic finding of noncaseating epithelioid cell granulomas. The disease has a predilection for intrathoracic structures; the musculoskeletal system is less frequently involved. Most osseous lesions in sarcoidosis are visible in the small joints of the hands and feet. Articular disease may present as an acute or chronic polyarthritis. Muscle involvement in sarcoidosis is generally asymptomatic. Neurologic findings of the central and peripheral nervous systems may occur in sarcoidosis. Subcutaneous nodules are of diagnostic value. Sarcoid vasculitis may involve small and large blood vessels. Sarcoidosis of the exocrine glands may mimic Sjögren's syndrome. Spontaneous remission of disease often occurs. Treatment with nonsteroidal anti-inflammatory agents, corticosteroids, antimalarials, radiation therapy, and immune-modulating drugs may be beneficial in the treatment of sarcoidosis.

Familial Chronic Lymphocytic Leukemia234

Chronic lymphocytic leukemia (CLL) was previously documented in a father and 4 of his 5 offspring. Follow-up studies revealed spontaneous regression of the disease in 1 patient and shifts in the clinical patterns in the other patients; the unaffected sibling developed lung adenocarcinoma. Cell surface analysis showed that 2 of these patients shared a common surface immunoglobulin profile with mu- and delta-type heavy chains and kappa-type light chains, whereas a 3d sibling with CLL had elevated mu- and kappa-chains. The patient with spontaneous disease remission had a perturbation in the percentage of cells bearing these same markers, consistent with a subclinical persistence of her lympho-proliferative process. Immunogenetic markers were associated with the occurrence of CLL, but these B-cell alloantigens were not linked to HLA. Two patients had abnormalities of chromosome 12 in B- but not T-cells: One had trisomy 12; the other had a mixture of dicentrics and translocations involving the same chromosome.

Vaginal intraepithelial neoplasia: Biologic aspects and treatment with topical 5-fluorouracil and the carbon dioxide laser

A review of 41 evaluable patients was made in order to study vaginal intraepithelial neoplasia (VAIN) and to investigate new methods of treatment. Colposcopic examination of the vagina revealed white epithelium alone in 20 patients and white epithelium associated with vascular punctation in 15. No lesion had a vascular mosaic pattern. Most patients had multifocal disease located in the vaginal apex. Iodine staining was positive in six patients with negative colposcopic examinations. Twenty-four patients had severe dysplasia or carcinoma in situ, and 17 had minimal or moderate dyplasia. Associated genital disease occurred in 17 patients with antecedent cervical or vulvar squamous neoplasia, and six additional patients had coexistent lesions. The chronology of vaginal disease that appeared after treatment of cervical neoplasia suggests a persistent but decreasing likelihood of the development of VAIN with the passage of time. In patients followed without therapy, six had spontaneous remission of disease. Treatment was successful in 12 of 15 patients with topical 5-fluorouracil and in nine of 10 patients with the carbon dioxide laser. The advantages of these methods of treatment for patients with VAIN relative to surgical procedures and radiation therapy are considered.

Experimental allergic encephalomyelitis in cyclophosphamide-treated Lewis rats: Clinical remissions and relapses and effect of treatment on neuro-fibrin deposits

Clinical remissions were observed in the majority of Lewis rats with experimental allergic encephalomyelitis (EAE) treated with cyclophosphamide (CY) at levels of 10 mg/kg or 20 mg/kg for 2–3 wk. Clinical relapses occurred in most survivors soon after the drug was stopped. Beneficial effects of CY therapy would appear to lie largely in helping rats survive the acute phases of EAE, but are offset by a high incidence of spontaneous remission of disease in untreated animals and the inevitable effects of drug toxicity. CY treatment at a dose of 5 mg/kg for 10 days may reverse both clinical signs and cellular infiltrates of EAE but does not inhibit the neurofibrin deposits characteristic of the disease. Remission of EAE in CY-treated and untreated Lewis rats is discussed in terms of multiplicity of immune responses to different neuroantigenic determinants.