Evidence Of Autoimmune Disease Research Articles

Genetic Analysis of Asymptomatic Antinuclear Antibody Production.

Antinuclear antibodies (ANA) are detected in up to 14% of the population, and many individuals with ANA are asymptomatic. The literature on the genetic contribution to asymptomatic ANA positivity is limited. In this study, we aimed to perform a genome-wide association study of asymptomatic ANA positivity in multiple populations. Asymptomatic individuals who were either ANA positive or ANA negative from the All of Us Research Program were included in this study, selecting those with an ANA test performed by immunofluorescence and no evidence of autoimmune disease. Imputation was performed, and a multipopulation meta-analysis including approximately 6 million single-nucleotide polymorphisms (SNPs) was conducted. Genome-wide SNP-based heritability was estimated using the Genome-wide Complex Trait Analysissoftware. A cumulative genetic risk score for lupus was constructed using previously reported genome-wide significant loci. A total of 1,955 asymptomatic ANA positive and 3,634 asymptomatic ANA negative individuals across three populations were included. The multipopulation meta-analysis revealed SNPs with a suggestive association (P <1 × 10-5) across 8 different loci, but no genome-wide significant loci were identified. A gene variant upstream of HLA-DQB1, (rs17211748, P = 1.4 × 10-6, odds ratio 0.82, 95% confidence interval 0.76-0.89), showed the most significant association. The heritability of asymptomatic ANA positivity was estimated to be 24.9%. Individuals who were asymptomatic and ANA positive did not exhibit increased cumulative genetic risk for lupus compared with individuals who were ANA negative. ANA production is not associated with significant genetic risk and is primarily determined by environmental factors.

Acute polyarthritis after astay in the Caribbean

A59-year-old female patient presented with acute polyarthritis after aholiday in the Caribbean. In addition, constitutional symptoms as well as myalgia and arthralgia were reported. Imaging demonstrated synovitis of the wrist and fingers without erosive changes. Immunoserological findings were normal with no evidence of autoimmune disease or vasculitis. Further evaluation revealed serological evidence of chikungunya virus infection.

Genetic analysis of asymptomatic antinuclear antibody production.

Antinuclear antibodies (ANA) are detected in up to 14% of the population and the majority of individuals with ANA are asymptomatic. The literature on the genetic contribution to asymptomatic ANA positivity in the population is limited. In this study, we aimed to perform a multi-ancestry genome-wide association study (GWAS) of asymptomatic ANA positivity. Asymptomatic ANA positive and negative individuals from the All of Us Research Program were included in this study, selecting those with an ANA test by immunofluorescence and no evidence of autoimmune disease. Imputation was performed and a multi-ancestry meta-analysis including approximately 6 million single-nucleotide polymorphisms (SNPs) was conducted. Genome-wide SNP based heritability was estimated using the GCTA software. A cumulative genetic risk score for lupus was constructed using previously reported genome-wide significant loci. 1,955 asymptomatic ANA positive and 3,634 asymptomatic ANA negative individuals were included across three genetic ancestries. The multi-ancestry meta-analysis revealed SNPs with a suggestive association (p-value < 1×10 -5 ) across 8 different loci, but no genome-wide significant loci were identified. A gene variant upstream of HLA-DQB1 (rs17211748, P = 1.4×10 -6 , OR = 0.82, 95% CI 0.76-0.89) showed the most significant association. The heritability of asymptomatic ANA positivity was estimated to be 24.9%. Asymptomatic ANA positive individuals did not exhibit increased cumulative genetic risk for lupus compared to ANA negative individuals. ANA production is not associated with significant genetic risk and is primarily determined by non-genetic, likely environmental, factors.

P1139 Lymphocytic Colitis: A large case series in the United Kingdom

Abstract Background Lymphocytic colitis, a type of microscopic colitis, was previously thought to be a rare condition. It is a histological diagnosis characterised by chronic loose stools and normal findings on endoscopy. It is now thought that it could be implicated in up to 10% of people with chronic diarrhoea, and has traditionally been associated with certain medications. We conducted a retrospective case analysis of patients diagnosed with the condition on histology between January 2018 till December 2022. Methods A list of patients who had undergone colonoscopy and biopsy for chronic diarrhoea, with no evidence of inflammatory bowel Disease (IBD), was generated. The patient’s electronic health records were then manually analysed, and data was collected using certain parameters including presence of autoimmune disease, faecal calprotectin levels/QFIT, smoking status, medication use (NSAIDS, PPI, Statins or SSRIs), colonoscopy findings, treatment choice and treatment outcomes. 121 patients were eligible based on histopathology consistent with a diagnosis of lymphocytic colitis. Results The median age was 63, with a 3:2 split of female to male patients. 63% reported painless, chronic diarrhoea lasting more than 6 weeks. 10.7% had painless and bloody diarrhoea, 23% had diarrhoea with abdominal pain. 25.4% had evidence of autoimmune disease. 43% were taking a PPI, 6.6% and NSAID, 41% a statin and 25.6% an SSRI. 27% were active smokers at the time of presentation. 62.8% of patients had a normal colonoscopy report, with the rest having ‘’abnormal reports” due to polyps. Faecal calprotectin levels ranged from 20-954. QFIT was positive in 35% of patients. 34% of patients were treated under a gastroenterologist. Of those who received budesonide only: 46% recovered with no relapse, 20% had relapsed in under 6 months, 16% relapsed after 6 months, 16% did not present again. Of the patients who received loperamide only, 66% reported resolution of symptoms. All histology demonstrated lymphocytosis in the lamina propria, 16% had expansion of the subepithelial collagen band, often termed ‘incomplete Microscopic colitis’. Conclusion Use of PPIs, statins and SSRIs are highly represented in the data, compared with general population usage. Treatment with either budesonide or loperamide generally lead to better symptom control, indicating patients should be referred to gastroenterology upon diagnosis. Clinicians should judiciously prescribe the above medications with clear indication and avoid prescribing indefinitely.

Are Patients with HHV-8 Associated Castleman Disease Successfully Treated with Rituximab at Risk of Subsequently Developing HHV-8 Negative (Idiopathic) Castleman Disease?

Multicentric Castleman disease (MCD) is a lymphoproliferative disorder characterized by lymph node histopathology and systemic symptoms. To our knowledge, there are no descriptions in the literature of long-term outcomes of human herpesvirus-8 (HHV-8)-associated MCD. We report a case of a 70-year-old male living with human immunodeficiency virus and a history of human herpesvirus-8 (HHV-8)-associated MCD. The patient reported having had low-grade fever for two weeks. Extensive workup revealed systemic lymphadenopathy without evidence of autoimmune disease or malignancy. Lymph node biopsy was consistent with HHV-8-negative idiopathic MCD (iMCD). The patient was subsequently scheduled for anti-interleukin-6 therapy. The present case is the first report of probable development of iMCD after long-term follow-up for HHV-8-associated MCD. The case illustrates the possible long-term consequences of MCD, suggesting the necessity of further research on the pathogenesis of CD. Given the uncertainty in the long-term outcomes of HHV-8-associated MCD, periodic surveillance of patients with a history of HHV-8-associated MCD is warranted. Prospective nationwide cohort studies comparing characteristics of HHV-8-associated MCD and iMCD would bring further insights. This is the first case describing the probable development of HHV-8-negative idiopathic MCD after HHV-8-associated MCD.Little is known of long-term outcomes of HHV-8-associated MCD and idiopathic MCD, necessitating periodic surveillance.HHV-8-negative idiopathic MCD patients are treated with siltuximab, an interleukin-6 inhibitor, unlike patients with HHV-8-associated MCD, who benefit most from rituximab.

Clinical and Immunological Characteristics of Patients with Biopolymers and Autoimmune Inflammatory Syndrome Induced by Adjuvants.

Background:Biopolymers consist of non-biocompatible allogeneic materials. They have been associated with autoimmune inflammatory syndrome induced by adjuvants, as described by Yehuda Shoenfeld and Nancy Agmon-Levin. Therefore, this study aimed to evaluate the clinical and immunological characteristics of patients with autoimmune inflammatory syndrome induced by adjuvants treated at a plastic surgery clinic in Colombia.Methods:This cross-sectional, descriptive observational study included 190 patients with biopolymers in the buttocks with no evidence of autoimmune disease who were diagnosed with autoimmune inflammatory syndrome induced by adjuvants and underwent treatment at a private plastic surgery clinic from 2017 to 2020. The clinical and paraclinical parameters were measured preoperatively, when the diagnosis of autoimmune inflammatory syndrome induced by adjuvants and the need for material removal were established, and postoperatively after 3 months.Results:The most frequent symptoms were myalgia (92%), arthralgia (77.9%), asthenia (77.9%), adynamia (77.9%), and neurological symptoms (55.8%). Preoperatively, patients were positive for antinuclear antibody, lactate dehydrogenase, complement proteins C3 and C4, and lupus anticoagulant. However, after removal of the biopolymer, there was a decrease in positivity or conversion to a negative status of paraclinical tests. Moreover, there was an association between LDH positivity and disease severity (odds ratio: 4.1, 95% confidence interval: 1.94–8.92).Conclusions:The removal of biopolymers using an open surgical technique in symptomatic or asymptomatic patients is crucial for functional and reconstructive purposes and to improve the quality of life. Therefore, this condition should be known as “human adjuvant disease caused by biopolymers.” Further, this condition mimics autoimmune diseases, with clinical and paraclinical manifestations that improve biopolymer removal.

Real-world prevalence of autoimmune disease (AD) among patients (pts) receiving immune checkpoint inhibitors (ICI) in ASCO’s CancerLinQ database.

6583 Background: Although pts with AD are routinely excluded from ICI clinical trials, evidence suggests they may be receiving ICI therapy once approved. We sought to understand the prevalence of AD among all pts receiving ICIs in real world clinical care, as well as in advanced non-small cell lung cancer (aNSCLC) alone, and to describe the characteristics of ICI pts with and without evidence of AD. Methods: We conducted a retrospective, observational cohort study using statistically de-identified data from January 2011 to November 2018 in CancerLinQ, ASCO’s real-world oncology database. Adult pts who received ≥ 1 dose of an ICI and had ≥ 2 clinical visits were eligible for inclusion. A sub-analysis examining only aNSCLC pts was also carried out. To reduce the likelihood of capturing pts who may have been on a clinical trial, pts were excluded if they received the ICI prior to its first FDA approval date. AD status was determined by the presence of select ICD-9/ICD-10 codes or a medication used to treat autoimmune disease (including steroids) prior to ICI treatment start date. Symphony claims data were linked to CLQ via tokenization to build out cohorts. Characteristics of pts with and without autoimmune disease were compared using Chi-square or Fisher’s exact tests. Results: Prevalence of AD was 23% (538/2425 pts) in the aNSCLC population and 27% (3407/12712 pts) in the all ICI patient population. Median age did not differ between AD pts and those with no evidence of AD (All ICI: 67.6 v 67.3 years; aNSCLC: 68.5 v 67.9). AD pts were more likely to be female (All ICI: 46% v 40%, p &lt; 0.001; aNSCLC: 55% v 44%, p &lt; 0.001). Among all ICI pts, AD pts were less likely to be Stage IV (62% v 65%) or to have melanoma (4.6% versus 8.7%) compared to pts with no evidence of AD. The most common ADs among all ICI and aNSCLC patients were glucocorticoid deficiency (6.3% and 3.9%), rheumatoid arthritis (4.2% and 5.8%), and sacroiliitis (2.7% and 3.9%), respectively. Conclusions: This analysis of real-world data finds that a large proportion of pts receiving ICI may have pre-existing AD. Further examination is warranted to examine how AD status may impact outcomes.

Real-world outcomes of patients with advanced non-small cell lung cancer (aNSCLC) and autoimmune disease (AD) receiving immune checkpoint inhibitors (ICIs).

110 Background: Anecdotal and early evidence suggest ICIs are being used in patients with advanced malignancies and history of AD, despite such patients being typically excluded from traditional clinical trials. We compared the outcomes of patients with or without AD, all of whom had ICI treatment for aNSCLC. Methods: We conducted a retrospective, observational cohort study using de-identified, curated data in ASCO’s CancerLinQ. Patients with Stage III or IV NSCLC who received ≥1 dose of an ICI and had ≥2 visits from Jan 2011 to Nov 2018 were included. AD status prior to ICI treatment was identified using ICD-9/ICD-10 codes or AD medications (including steroids). Symphony claims data were linked via tokenization to build cohorts. Time to treatment discontinuation (TTD), time to next treatment (TTNT), real-world progression-free survival (rwPFS) and overall survival (OS) were compared across the two cohorts using the log-rank test. Cox Proportional Hazards Model was used to adjust for covariates. Adverse events (AEs) were compared using Chi-Square and Fisher’s Exact Test. Active AD was defined as evidence of autoimmune disease in the year prior to starting ICIs. Results: Among 2425 patients with aNSCLC treated with ICIs, AD was present in 22% (N=538). Median OS in all patients was 12.4 months (95% CI 11.3-13.5). TTD, TTNT, rwPFS and OS did not differ between the two cohorts (Table). There was no association between AD status and outcomes. There was no increased incidence of AEs in the AD group; however a sub-analysis among patients with active AD showed higher rates of select AEs including endocrine, GI and blood disorders. Conclusions: This analysis demonstrates that patients with evidence of AD prior to receiving ICI have similar outcomes compared to patients with no evidence of AD. Further research is needed to better understand the impact of active AD on the risk of AEs and patient outcomes. [Table: see text]

Paraneoplastic vasculitis in patients with metastatic renal cell carcinoma.

A paraneoplastic syndrome is observed in 5% to 10% of cancer patients. Paraneoplastic vasculitis (PV) in metastatic renal cell carcinoma (mRCC) patients has been poorly investigated. In our case series study, we evaluated the incidence and development of PV in patients with mRCC. Patients were required to have previously untreated clear-cell or papillary mRCC and no evidence of autoimmune diseases or venous thrombosis in history. Patients had a careful examination including Doppler ultrasonography of the blood vessels and skin punch biopsy in the presence of suspicious skin rash. Sixteen (8.2%) of 196 patients were diagnosed with PV, which was manifested clinically by leukocytoclastic vasculitis on the lower extremities. Skin biopsy confirmed vasculitis. Progression-free survival and overall survival were significantly better in patients without PV. PV is not rare paraneoplastic syndrome in mRCC. Leukocytoclastic vasculitis was the most common type of PV in this study.

Familial diabetes of adulthood: A bin of ignorance that needs to be addressed

AimsThe aim of this article was to share with a wide readership some data and related reasoning about a multigenerational form of diabetes mellitus of adulthood. Data synthesisWe have recently described a familial form of diabetes mellitus, which in the routine clinical setting of adult individuals is simplistically diagnosed as type 2 diabetes. Such misdiagnosis involves as much as 3% of adult unrelated diabetic patients with no evidence of autoimmune disease. More recent data, obtained by means of a next-generation sequencing, indicate that approximately 25% of such patients carry mutations in the genes involved in monogenic diabetes, thus leaving unraveled the molecular causes of the remaining 75% individuals. ConclusionsOur proposal is to define the latter patients as being affected by familial diabetes of adulthood (FDA), a clear admission of ignorance and a limbo where adult patients with multigenerational diabetes with no genetic definition of their hyperglycemia have to wait for better times.

Adult idiopathic cholestasis: a condition more common in the Canadian Inuit?

ABSTRACTDespite extensive investigations, some patients have no identifiable cause for their cholestatic liver enzyme abnormalities. The aim of this study was to document the clinical, laboratory, radiologic and histologic features of adult patients with idiopathic cholestasis (AIC). A computerised database of referred patients to a tertiary care hospital outpatient department for assessment of hepatobiliary disorders between 2005 and 2015 was employed to identify and describe features associated with AIC. Of 6,560 patient referrals, sufficient documentation to warrant a diagnosis of AIC was present in 17 (0.26%) cases. Of the 17, a disproportionate number were Canadian Inuit (7/60, 12% Inuit referrals vs. 10/6,500, 0.16% non-Inuit referrals, p<0.0001). The median age of the 17 subjects was 57 years and nine (53%) were female. Clinical and/or laboratory evidence of autoimmune disorders was present in six (35%) cases. Clinical features of hepatic decompensation, radiologic findings in keeping with cirrhosis and histologic confirmation of cirrhosis were present in 47%, 31% and 42% of individuals, respectively. There were no significant improvements in cholestatic liver enzymes and function tests in those treated with ursodiol and/or immunomodulants (n=7) compared to those left untreated (n=10). In conclusion, AIC is a rare condition diagnosed by exclusion. It appears to be more common in the Canadian Inuit population and those with autoimmune disorders. Advanced liver disease is a frequent finding at presentation. Intervention with ursodiol and/or immunomodulants does not appear to be of therapeutic value.

Identification of a Th2- and Th17-skewed immune phenotype in chronic urticaria with Th22 reduction dependent on autoimmunity and thyroid disease markers.

Chronic urticaria is a condition with many inciting factors and often presents a therapeutic challenge to clinicians. In addition to a central role for mast cells, an immune dysregulated state related to cytokine/chemokine alterations is increasingly being recognized. Biopsies of chronic urticaria (n = 11) and normal skin (n = 5) were evaluated with immunostains for CD117, CD3 and dual stains for CD4/T-bet, GATA-3, STAT-3 or BNC-2 (transcription factors specific and mutually exclusive for Th1, Th2, Th17 and Th22 cells, respectively). Clinical data, including autoantibodies and thyroid function tests, and the number of CD117+ mast cells and percent of Th1, Th2, Th17 and Th22 of CD3+ T-cells were compared. Th2 cells and Th17 cells were significantly more frequent in chronic urticaria than controls. In contrast, there was no significant difference in mast cells, Th1 cells or Th22 cells. Three of nine chronic urticaria patients had evidence of autoimmune disease; biopsies from these patients trended toward a greater number of mast cells and decreased percent of Th-cell subtypes as compared with those without autoimmunity markers, with significantly less Th22 cells. These findings provide novel insight into the role of Th2 and Th17 in chronic urticaria pathophysiology and may impact therapy.

NLRP3 Inflammosome Polymorphisms Are Enriched in Myelodysplastic Syndrome Patients with Autoimmune Disorders

Autoimmune disorders (AIDs) are commonly observed in up to 30% of myelodysplastic syndromes (MDS) patients. Clinical manifestations such as acute neutrophilic febrile dermatosis, rheumatoid arthritis, inflammatory bowel disease, pulmonary infiltrates and peripheral polyneuropathy, precede or accompany the diagnosis of MDS. In fact, large-scale epidemiologic studies have suggested that patients with AIDs have an elevated risk of developing MDS.To gain more insight into the association of MDS and AIDs, bone marrow mononuclear cells available from 202 patients were sequenced for 'inflammsome' pathway genes NLRP3 and MYD88, which have been shown to carry mutations in various AIDs. According to WHO classification, the patient cohort included 49% RA/RARS/RCMD, 24% RAEB, 6% 5q syndrome, 10% AML, 6% MPD/MDS and 5% tMDS. Median age of the cohort was 62 years (IQR 54.8-62.3). Autoimmune data was available on 129 patients and 49/129 patients had evidence of AID. 31 patients were diagnosed with MDS-associated 'Sweets Syndrome' AID. Myeloid neoplasm-related 22 gene panel mutation data was available for 171 patients.Initially all protein coding exons of NLRP3 and MYD88 genes were sequenced in 31 cases diagnosed with MDS-Sweets syndrome. Targeted sequencing (Miseq, Illumina) revealed NLRP3 variants in 6/31 cases. NLRP3 heterozygous variants detected were V200M (n=1/31, 3%), Q705K (n=4/31, 13%) and T954M (n=1/31, 3%). Two of these variants (V200M and Q705K) have been previously described as pathogenic and linked with various autoimmune disorders1,2. Variant T954M is reported in COSMIC v73 database as a confirmed somatic mutation. The frequency of these variants in general European population (NHLBI ESP 2015) varies in-between 0.6% to 5% (V200, rs121908147 MAF= 0.7%; Q705, rs35829419 MAF= 5% and T954, MAF= <0.1%). None of the patients sequenced in our study had MYD88 gene mutations. Therefore, we decided to perform targeted amplicon sequencing on three codons (V200, Q705 and T954) of the NLRP3 gene in remainder of the 171 cases.NLRP3 heterozygous variants V200M and Q705K were observed in 2.3% (n=4/171) and 12% (n= 20/171), of the patients screened, respectively. T954M variant was not detected in the follow-up cohort. Sequencing of the paired constitutional DNA (CD3+ lymphocytes/ Skin biopsy), where available (n=10), confirmed that V200M and Q705K are inherited SNPs. The frequency of these NLRP3 variants observed among our study population is marginally higher than previously described in the general European population (Pearson chi-square test, P >0.05)In order to detect the effects of the NLRP3 variant on the inflammasome pathway, we quantified the serum cytokine (IL1β, IL18, TNFα and INFγ) levels using ProcartaPlex Human Cytokine & Chemokine Panel 1A (34 plex, eBioscience) kit in patients with NLRP3 variants (MDS/sweets syndrome, n =3) vs NLRP3 wildtype (MDS-Sweets syndrome, n=5; MDS/non-sweets syndrome, n=2). No difference was observed in the serum cytokine levels between two patient groups. Next, we investigated the mRNA levels of the NLRP3 and other genes that lie downstream of the NLRP3 inflammasome pathway (IL1β, IL18, TNFα, CASPASE-1 and INGγ). 34 patients (NLRP3 variant, n= 22 and NLRP3 Wildtype, n= 12) were included in this analysis. An increased trend in the IL18 mRNA levels was observed in patients with NLRP3 variant vs NLRP3 wildtype.In conclusion, our study shows that the NLRP3 variants are enriched in MDS patients with AIDs compared to historical data on the general population. Patients with NLRP3 variants have an increased levels of IL18 mRNA levels. A larger study to explore the inflammasome pathway is needed to define the molecular pathogenesis of the autoimmunity associated with MDS. Identifying the casual genomic variants of AIDs in MDS may provide relevance to development of novel therapeutic strategies.

No Evidence of Autoimmune Disorders in Antiretroviral-Experienced HIV-1-Infected Individuals after Long-Term Treatment with Raltegravir

The HIV integrase inhibitor raltegravir (RAL) can exacerbate autoimmune diseases in genetically predisposed mice. To evaluate whether this may occur in clinical practice, we clinically monitored HIV-positive patients treated with RAL and measured a panel of autoantibodies (auto-Abs) during the first year of RAL treatment. This was a longitudinal study in 109 antiretroviral-experienced patients who started a RAL-based regimen and were followed up for more than 2 years. A total of 45 patients were tested at baseline (before starting RAL) and after 12 months for the presence of the following auto-Abs: anti-nuclear antibodies, anti-double-stranded DNA, anti-smooth-muscle antibodies, anti-thyreoglobulin and anti-thyroid peroxidase antibodies, anti-cardiolipin immunoglobulin G and immunoglobulin M and anti-nuclear extractable antigens, including anti-SM ribonucleoprotein antigen, anti-Ro antigen and anti-La antigen. A low rate of clinically relevant autoimmune diseases was observed at study entry (3/109; 2.8%; 95% CI 0.004, 0.059). No exacerbations were observed during follow-up. During the second year of RAL-based therapy a previously healthy patient developed psoriasis. At baseline, 17/45 (37.8%) patients tested for the presence of auto-Abs were positive. Most patients (n=13) were positive for anti-cardiolipin. After 12 months of RAL exposure, 9/45 patients were positive (20%; P=0.063). A positive correlation was found between HIV-1 RNA and anti-cardiolipin antibody concentration (P=0.010). According to these results, RAL does not promote antibody-mediated immune disorders, at least not in the mid-term. A prolonged follow-up and an extension of the panel of auto-Abs are recommended to support these results.

Selective IgM deficiency in an adult presenting with Streptococcus pneumoniae septic arthritis

Septic arthritis caused by Streptococcus pneumoniae is uncommon. Most of the patients who have invasive pneumococcal infection have underlying diseases associated with impaired immune function. We report a case of polyarticular pneumococcal septic arthritis in a previously healthy adult as the first manifestation of selective immunoglobulin (Ig)M deficiency. The patient had no evidence of autoimmune disease or malignancy. Serum IgG, IgA, and complement levels were normal. Numbers of lymphocyte subsets were in normal range except that of CD4+ cells, which was slightly low. Invasive pneumococcal disease in a healthy adult should lead to further investigation for underlying diseases including primary immunodeficiencies.

Defining the aromatase inhibitor musculoskeletal syndrome: A prospective study

To define the musculoskeletal syndrome associated with use of aromatase inhibitors (AIs), specifically, to describe its incidence, time to onset, risk factors, and clinical presentation. Postmenopausal women with hormone-sensitive, nonmetastatic breast cancer starting AI therapy were enrolled in this prospective cohort study. They underwent complete rheumatologic evaluation and contrast-enhanced magnetic resonance imaging (MRI) of the hands and wrists prior to starting AI, at 3 and 6 months. The primary outcome was change in grip strength. Twenty-eight (54%) of 52 women reported new or worsening musculoskeletal symptoms. Two discontinued AIs due to pain. Mean time to symptom onset was 6 weeks (range 2-18 weeks), and 75% of symptomatic patients developed symptoms by 8 weeks. Later-stage cancer and worse quality of life (QOL) pretreatment were significantly associated with symptom development. Sixty-eight percent of symptomatic subjects had involvement of the hands; however, there was no difference in the mean change in grip strength (-2.9 kg versus -1.3 kg; P = 0.6). Among symptomatic subjects, 46% had evidence of focal tenosynovitis of the hands and feet on examination. Although some symptomatic subjects had new MRI abnormalities, Rheumatoid Arthritis Magnetic Resonance Imaging Scoring did not significantly change. The incidence of AI-associated musculoskeletal syndrome is more than 50%, with most women developing symptoms by 8 weeks. The key finding in symptomatic women was focal tenosynovitis of the hands and feet, without evidence of autoimmune disease or systemic inflammation. Later-stage cancer and poorer QOL were predictive of symptom development.

Autoimmune phenomena in untreated and treated marginal zone lymphoma

Introduction: Current literature suggests an association between various autoimmune conditions and marginal zone lymphoma (MZL). However, these autoimmune conditions have not been comprehensively systematized to date. As a result, their clinical implications remain largely unknown.Areas covered: The authors provide a comprehensive review of the existing literature on various autoimmune abnormalities documented in the course of MZL, as well as on autoimmune alterations induced by certain MZL therapies.Expert opinion: The course of MZL is accompanied by a variety of hematologic and non-hematologic autoimmune disorders. Whereas some of them could be secondary and related to the course of the MZL, others may be primary and might even favor the development of MZL itself. In addition, authentic autoimmune conditions have been documented with the use of rituximab as a single agent and the nucleoside analogs. Therefore, we believe caution should be exerted with the use of these agents in MZL patients with evidence of autoimmune disorders, as exacerbation of autoimmune phenomena can be anticipated. While the heterogeneity of the MZL subtypes represents an inherent limitation, integration of emerging information from immunology research laboratories and clinical practice could translate into improved outcomes of this disease spectrum.

Immune alterations in untreated and treated myelodysplastic syndrome

Introduction: Current literature suggests a variety of immune abnormalities are present in myelodysplastic syndrome (MDS) patients. However, they have not been comprehensively characterized or systematized to date. As a result, their clinical implications remain largely unknown. In addition, an increased incidence of various autoimmune conditions has been documented in MDS patients.Areas covered: The authors offer a comprehensive review of the existing literature on immune mechanisms involved in the pathogenesis of MDS, various immune abnormalities documented in its course, their link with the clonal evolution of MDS as well as immune alterations induced by the existing MDS therapies.Expert opinion: The course of MDS is accompanied by complex immune alterations, including T-cell and NK-cell defects, decreased functional abilities of neutrophils and antigen-presenting cells, altered antibody and cytokine production. While contemporary MDS therapies are shown to possess some immunomodulatory properties, authentic autoimmune conditions have also been documented with lenalidomide and recombinant erythropoietin. Caution should be exerted with the use of these agents in MDS patients with evidence of autoimmune disorders, as exacerbation of autoimmune phenomena can be anticipated. While the heterogeneity of MDS represents an inherent limitation, integration of emerging information from molecular biology, genetics, immunology research and clinical practice could translate into improved outcomes of this disease spectrum.

ORIGINAL ARTICLE: Autoimmunity predominates in a large South African cohort with addison’s disease of mainly European descent despite long‐standing disease and is associated with HLA DQB*0201

We sought to determine whether autoimmunity is the predominant cause of Addison's disease in South Africa and whether human leucocyte antigen (HLA) DQ association exists. We compiled a national registry of patients from primary care, referral centres and private practices. A total of 144 patients, 94 of European descent, 34 Mixed Ancestry, 5 Asian and 11 Black Africans (mean age 45.9 years, range 2.7-88 years; mean duration of disease 13.1 years, range 0-50 years) and controls were matched for gender and ethnicity. All potential causes were investigated. Fifty one per cent of cases (74 patients) were autoimmune in aetiology. Either 21-hydroxylase autoantibodies (72 patients, 50% of entire patient group) or adrenocortical autoantibodies (35 patients, 24%) were present, while 23% of patients had both. None of the Asian (n = 5) or Black (n = 11) patients had evidence of autoimmune disease. Overall 8% of patients had tuberculosis, 4% adrenoleucodystrophy, 1% adrenocorticotrophic hormone resistance syndrome and 6% X-linked adrenal hypoplasia. In those with autoimmune disease primary hypothyroidism (47%), premature ovarian failure (8%) and type 1 diabetes (7%) were the most prevalent accompanying autoimmune conditions. HLA DQB1*0201 alleles predominated in the autoimmune group (DQB1*0201: 65%vs 43% of controls P = 0.017) with the *0201/*0302 heterozygous genotype being the most prevalent (28%vs 8%P = 0.02). While autoimmunity accounts for at least half of patients with Addison's disease in South Africa and is associated with HLA DQB1*0201, none of the Black Africans or Asians in this cohort had adrenal autoantibodies. Moreover, 21-hydroxylase autoantibodies were detectable in a higher proportion than adrenocortical autoantibodies, especially in those patients with a long history after disease onset.

Abstract C228: Renal insufficiency secondary to Erlotinib: Is it real?

Abstract Objective: We conducted a retrospective chart review to assess the extent of renal insufficiency noted in patients receiving Erlotinib for refractory/relapsed non small cell lung cancer at our Institute. Methods: We reviewed the charts of 285 patients at Roswell Park Cancer Institute, who received Erlotinib for varying durations of time during 2004 and 2009. Baseline and post-erlotinib serum creatinine (SCr) and serum creatinine clearance (SCrCl) levels were noted. Cases with worsening of serum creatinine levels during treatment with erlotinib were isolated. Extent of worsening, associated co-morbidities and medications and other factors possibly contributing to renal dysfunction were noted along with improvement in renal status after discontinuation of erlotinib. Results: Of the 175 patients with data available for evaluation, 21(12%) had worsening of their baseline SCr level while on erlotinib. 13(62%) of the patients with renal insufficiency had documented hypertension as co morbidity and were on anti-hypertensives including diuretics and ACE inhibitors. 8(38%) were diagnosed with diabetes mellitus and 6(28%) had coronary artery disease. 6(28%) patients had established chronic renal insufficiency (CRI) at baseline and had worsening after initiation of erlotinib. 1 patient had CRI secondary to prior history of renal cell cancer and was post nephrectomy. 1 patient had evidence of autoimmune disorder with Reynaud's phenomenon and polycystic kidneys. Another patient had history of lupus without evidence of CRI at baseline. 6(28%) concomitantly had diarrhea as a side-effect with erlotinib and in at least 3(14%) patients was the reason for discontinuation of further drug administration. In the remainder of the patients, the cause of discontinuation of erlotinib was progression in 13(52%), severe rash in 2(9%) and 3(14%) were still on the drug at the time of this analysis. Overall 5(21%) of patients with renal insufficiency after initiation of erlotinib did not have any other confounding factors identified. The onset of worsening renal status ranged from 14 days up to 333 days with a mean of 60 days. Baseline SCrCl of patients ranged from 26.2 to 100.5 ml/min with a mean of 49.8 and baseline SCr levels ranged from 0.9 to 2.4 mg/dl. Post therapy SCrCl in patients with worsening ranged from 18.5 to 59.8 with a mean of 35.9 and SCr levels from 1.3 to 3.4. Hence mean decline in SCrCl in these patients was by approximately 14 ml/min and serum creatinine of 0.5mg/dl. Of the 19 patients not currently on erlotinib any more, 12(63%) were noted to have improvement in SCrCl in mean of 33 days. Conclusion: The incidence of isolated renal insufficiency due to erlotinib is rare but does exist. Most often it is confounded with preexisting hypertension and diabetes mellitus leading to baseline chronic renal dysfunction and multiple other medications or concomitant diarrhea as a side effect of erlotinib leading to pre-renal worsening of kidney function. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C228.