Stanley P. Ballou

Induction of inflammatory cytokine release from cultured human monocytes by C-reactive protein.

The human acute phase protein, C-reactive protein (CRP), is capable of specifically binding to and modulating the function of mononuclear phagocytes. To investigate whether CRP can also affect the capacity of these cells to produce inflammatory cytokines, enzyme immunoassays and Western blot techniques were used to quantitate interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) produced by freshly-isolated normal human monocytes. CRP induced the rapid release of each cytokine, with significantly elevated levels in culture supernatants at 4 hours and maximal levels of TNF-alpha at 8 hours, and of IL-1 beta and IL-6 at 16 hours of culture. The effects of CRP were dose-dependent; greater than 10-fold increases of each cytokine were observed following culture with greater than or equal to 50 micrograms/ml CRP, concentrations which are often found in the presence of moderate to severe inflammation or tissue injury. The induction of cytokine release by CRP was unaffected by inclusion of 25 micrograms/ml polymyxin-B in culture media, but was completely abrogated by prior boiling of the CRP, a procedure which had no effect on induction of monocyte cytokine release by lipopolysaccharide. The dose-dependent induction of inflammatory cytokines by CRP provides further support for the hypothesis that interaction with mononuclear phagocytes constitutes an important biological role for this acute phase protein.

Abetimus sodium for renal flare in systemic lupus erythematosus: Results of a randomized, controlled phase III trial†

OBJECTIVE To investigate whether treatment with abetimus delays renal flare in patients with lupus nephritis. Secondary objectives included evaluation of the effect of abetimus on C3 levels, anti-double-stranded DNA (anti-dsDNA) antibody levels, use of high-dose corticosteroids and/or cyclophosphamide, and major systemic lupus erythematosus (SLE) flare. METHODS We conducted a randomized, placebo-controlled study of treatment with abetimus at 100 mg/week for up to 22 months in SLE patients. Three hundred seventeen patients with a history of renal flare and anti-dsDNA levels >15 IU/ml were randomized to a treatment group (158 abetimus, 159 placebo); 298 (94%) were enrolled in the intent-to-treat (ITT) population (145 abetimus, 153 placebo), based on the presence of high-affinity antibodies for the oligonucleotide epitope of abetimus at baseline screening. RESULTS Abetimus did not significantly prolong time to renal flare, time to initiation of high-dose corticosteroid and/or cyclophosphamide treatment, or time to major SLE flare. However, there were 25% fewer renal flares in the abetimus group compared with the placebo group (17 of 145 abetimus-treated patients [12%] versus 24 of 153 placebo-treated patients [16%]). Abetimus treatment decreased anti-dsDNA antibody levels (P < 0.0001), and reductions in anti-dsDNA levels were associated with increases in C3 levels (P < 0.0001). More patients in the abetimus group experienced > or =50% reductions in proteinuria at 1 year, compared with the placebo group (nominal P = 0.047). Trends toward reduced rates of renal flare and major SLE flare were noted in patients treated with abetimus who had impaired renal function at baseline. Treatment with abetimus for up to 22 months was well tolerated. CONCLUSION Abetimus at 100 mg/week significantly reduced anti-dsDNA antibody levels but did not significantly prolong time to renal flare when compared with placebo. Multiple positive trends in renal end points were observed in the abetimus treatment group.

Diffuse Intervertebral Disk Calcification in Primary Amyloidosis

Excerpt Diffuse calcification of many lumbar and thoracic intervertebral disks has been thought to be highly suggestive, if not pathognomonic, of ochronosis. A patient with widespread intervertebra...

Case Report Comparative response of fever to corticosteroids in tuberculosis and in connective tissue disease

A young woman with fever and pleural effusion eventually was found to have both primary tuberculosis and systemic lupus erythematosus. Before either diagnosis was confirmed, the patient had a dramatic defervescence in response to prednisone; her condition had not improved initially after anti-tuberculous therapy. Uncertainty regarding the clinical significance of this remarkable temperature response led us to review our experience with febrile tuberculous patients who had received corticosteroids. Of 14 such patients, nine had rapid declines of body temperature to below 36.5C. In a comparable group of 14 patients with a variety of connective tissue disease, 12 showed an equally dramatic defervescence after corticosteroid administration. The data suggest that a prompt temperature decline following corticosteroid therapy is a nonspecific response that cannot be used to differentiate between fever of infectious or noninfectious origin.

Markers of Inflammation and Rheumatology Tests–An Update for Internists

Importance: The rapid proliferation of laboratory tests related to rheumatology, the recent interest in C-reactive protein as a possible marker for cardiovascular disease risk, and the need to contain the costs of medical care by avoiding unnecessary testing have indicated the need for a review of these tests aimed at general internists. Objective: To provide internists with guidance for when to use specific rheumatology related laboratory tests. Evidence Review: Literature reviews as well as important rheumatology references were appraised in order to give an updated review of the rheumatology laboratory tests included in this review. Findings: Certain rheumatology tests should be employed when an internist suspects a particular autoimmune or connective tissue disease. Conclusions and Relevance: A detailed review of symptoms and examination is of primary importance, while laboratory tests usually serve to support or argue against possible diagnoses.

Triple Valvulopathy and Jaccoud’s Arthropathy: A Case Report and Literature Review

Cardiac involvement is fairly common in patients with systemic lupus erythematosus (SLE). It may involve all layers of the heart and coronary arteries as well as the heart valves. We report an extremely rare presentation of valvulitis and valvular dysfunction associated with systemic lupus erythematosus. This is the first case of lupus valvulitis which required three mechanical prosthetic valve replacements with disease recurrence leading to a fatal outcome. This is, in our point of view, the consequence of aggressive natural history of the disease and perhaps late diagnosis and treatment of underlying SLE which was unsuccessful.

Seronegative Rheumatoid Arthritis: A Case Control Study

Background : Seronegative Rheumatoid Arthritis (RA) is a disorder associated with considerable diagnostic, prognostic and therapeutic uncertainty for many clinicians. Objectives : The aim of this study is to elucidate clinical features at diagnosis, manifestations and treatment of patients with RA with negative serologies, as compared to a control group of patients presenting with similar polyarthralgias but diagnosed with alternative (non-RA) musculoskeletal disorders. Methods : The study was a retrospective chart review of electronic medical records from January 2003 to December 2012. Patients were identified using ICD-9 code Rheumatoid Arthritis 714.0 and at least two rheumatology clinic visits during the specified time. Charts were reviewed individually by two investigators. The inclusion criteria were a diagnosis of RA confirmed by a rheumatologist and normal values for both rheumatoid factor (RF) and anti-cyclic citrullinated protein antibodies (ACPA, third generation assay). Charts were also reviewed for eventual final diagnosis, either seronegative RA or alternate diagnosis (control group). Data were collected on demographics (sex, race, smoking status), family history of RA, and laboratory values (presence of anemia, inflammatory markers) at the time of diagnosis. The presence of erosions and synovitis identified by imaging studies was assessed. In addition, the presence of extra-articular manifestations of RA including nodules, pleural or parenchymal lung disease, eye involvement and osteoporosis was recorded. The therapies (disease modifying anti-rheumatic drug (DMARD), biologic) used to treat the seronegative RA were also reviewed. The family & smoking history and laboratory values of the seronegative RA patients were compared to the control group and analysis was done using Fisher’s exact test. Results : Charts from 107 patients were reviewed. Forty-four patients were eventually classified as having an alternate diagnosis and were considered the control group. Sixty-three patients were considered to have an established clinical diagnosis of seronegative RA. Among all patients at the time of diagnosis, 25% were smokers, 13% had a family history of RA, 54% were anemic, and 76% had abnormal ESR or CRP. The RA patients had statistically higher proportion with anemia compared to controls at presentation, and statistically lower proportion with ESR elevation compared to controls ( p =0.033 and p =0.013, respectively). Seven of the 59 (11%) patients who had hand/wrist films during their care had erosions on radiography, and 6 of 13 (46%) patients who had an MRI of an extremity had findings of synovitis. Extra-articular manifestations were infrequent in this group. Forty-eight of the 62 were initiated on a DMARD, most commonly hydroxychloroquine (16% patients) or methotrexate (29% patients) or a combination of methotrexate and hydroxychloroquine therapy (35%). Of the 63 patients, 17 (27%) patients required a biologic therapy during treatment course. Conclusions : This study supports the hypothesis that clinical history and physical examination can be important determinants in helping to diagnose seronegative RA and distinguish it from other polyarthopathies. In addition to characteristic symptoms, factors which might contribute to diagnosis of RA in a patient without seropositivity include presence of anemia, and results of imaging studies.

AB0240 The Effect of Anti Estrogen Therapy (AET) on Rheumatoid Arthritis

Background The musculoskeletal side effects of anti-estrogen therapy, especially Aromatase Inhibitors (AI), are now well established and the name AIA (Aromatase inhibitors induced arthralgia) has been proposed to describe actual inflammatory arthritis related to these medications (1). Recent observations by our group suggest increased incidence of RA among patients using either AI or selective estrogen receptor modulators (SERMs) (2) Objectives We intended to examine any effect of AET on disease activity in patients with established RA Methods We searched the electronic medical records in our facility using ICD-9 codes for all patients with the diagnoses of both breast cancer and Rheumatoid arthritis. We reviewed charts to isolate those with validated RA diagnosis who have used Tamoxifen or AI for breast cancer. The primary outcome measure was worsening of disease within 1-18 months after starting AET based on one or more of the following: Increased tender or swollen joint counts, addition of new DMARDs, withdrawal of AET because of worsening pain/swelling, and new onset RA. The worsening could not be attributed to changes or discontinuation of RA therapy. All data were extracted from Rheumatology clinic notes within 1-12 months of starting AET. Laboratory markers for inflammation were not considered because they were thought to be influenced by recent cancer diagnosis Results Fifteen patients were included in this analysis. Mean age was 59 years and median duration of RA prior to cancer diagnosis was 7.1 years. Old age and lung cancer were the cause of death in the 2 patients who expired. All patients but one had ductal carcinoma (in citu or infliltrative) with negative HER2 amplification. AET used included Tamoxifen (4), Anastrazole (10) and Lotreziole (1). Most patients were on stable DMARDs. One patient only was on biologic (abatacept) which was continued with no worseneing of her RA after AET initiation. Nine of 13 with available serology were seropositive; 2 of them developed new onset RA within a year of starting. RA worsened in 8 patients (54%) after initiating AET: 2 had new onset disease, 1 with flaring after years of remission, 1 had to stop AET (Anastrazole), 2 had to add/increase DMARDs and 2 had increased number of swollen/tender joints on expert assessment. One of the patients who used tamoxifen developed new onset RA starting with knees involvement while the other 3 did not have worsening of their established RA. With the use of AIs; 63% had worsening including 1 new onset RA with anastrasole. Among those who worsened, symptoms started within 2-5 months in most patient except 1 with later worsening (18 months later). On comparing patients who worsened to those who did not; patients with worsening tended to be younger (57 vs. 61: P=0.55) and had longer duration of disease (8.4 vs. 5.6 years P=0.5). Conclusions Our data suggest that use of AET may worsen disease activity in patients with rheumatoid arthritis as well as increasing the incidence of the disease. Young age and long disease duration for RA increased the trend for worsening. Our study is limited by the small number of patients References Niravath P. Aromatase inhibitor-induced arthralgia: a review. Ann Oncol. 2013 Jun;24(6):1443-9 Chen JY, Ballou SP. The Effect of Antiestrogen Agents on Risk of Autoimmune Disorders in Patients with Breast Cancer. J Rheumatol. 2014 Oct 1. Disclosure of Interest None declared

AB0326 Characterizing Seronegative Rheumatoid Arthritis

Background Seronegative Rheumatoid Arthritis (RA) is a disorder associated with considerable diagnostic, prognostic and therapeutic uncertainty for many clinicians. Objectives The aim of this study is to provide a deeper understanding of the diagnosis and manifestations of rheumatoid arthritis with negative serologies. Methods The study was a retrospective chart review of electronic medical records from January, 2003 to December, 2012. Patients were identified using ICD-9 code Rheumatoid Arthritis 714.0 and at least two rheumatology clinic visits during the specified time. Charts were reviewed individually by two investigators. The inclusion criteria were a diagnosis of RA confirmed by a rheumatologist with normal values for both rheumatoid factor (RF) and anti-CCP antibodies (CCP, third generation assay). Data were collected on demographics (sex, race, smoking status), family history of rheumatoid arthritis, and laboratory values (presence of anemia, inflammatory markers) at the time of diagnosis. The presence of erosions and synovitis identified by imaging studies was assessed. In addition, the presence of extra-articular manifestations of RA including nodules, pleural or parenchymal lung disease, eye involvement and osteoporosis was recorded. The therapies (DMARD, biologic) used to treat the seronegative RA were also reviewed. Results Charts from 108 patients were reviewed. Forty-five patients were excluded based on incorrect initial diagnosis or low clinical suspicion for seronegative RA by the rheumatologist. Sixty-three patients were included in this analysis. The demographics were similar to that of our patient population with seropositive RA. Of available data, at the time of diagnosis, 25% of the patients were smokers, 13% had a family history of RA, 54% were anemic, and 76% had abnormal ESR or CRP. Seven of the 63 (11%) patients had erosions on radiography, and 6 of 63 (9.5%) patients had MRI findings of synovitis. Initial data suggest that extra-articular manifestations are infrequent in this group. Forty-eight of the 62 were initiated on a DMARD, most commonly hydroxychloroquine (16% patients) or methotrexate (29% patients) with a large percentage of patients with combination of methotrexate and hydroxychloroquine therapy (35%). Of the 63 patients, 17 (27%) patients required a biologic therapy during treatment course. Conclusions This study supports the hypothesis that clinical history and physical examination are the most important determinants in diagnosing seronegative RA. In addition to characteristic symptoms, factors which might contribute to diagnosis of RA in a patient without seropositivity include positive family history, smoking history, acute phase reactants, presence of anemia, and imaging studies. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2163