Debendra Pattanaik

Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps

OBJECTIVE To test the hypothesis that autoantigen modifications by peptidylarginine deiminase type 4 (PAD-4) increase immunoreactivity. METHODS We assembled sera from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Feltys syndrome (FS), and antineutrophil cytoplasmic antibody-associated vasculitides (AAVs), as well as sera from control subjects without autoimmune diseases. The sera were tested for binding to activated neutrophils, deiminated histones, and neutrophil extracellular chromatin traps (NETs). IgG binding to lipopolysaccharide-activated neutrophils was assessed with confocal microscopy, and binding to in vitro-deiminated histones was measured using enzyme-linked immunosorbent assay (ELISA) and Western blotting. In addition, we quantitated histone deimination in freshly isolated neutrophils from the blood of patients and control subjects. RESULTS Increased IgG reactivity with activated neutrophils, particularly binding to NETs, was paralleled by preferential binding to deiminated histones over nondeiminated histones by ELISA in a majority of sera from FS patients but only in a minority of sera from SLE and RA patients. Immunoblotting revealed autoantibody preference for deiminated histones H3, H4, and H2A in most FS patients and in a subset of SLE and RA patients. In patients with AAVs, serum IgG preferentially bound nondeiminated histones over deiminated histones. Increased levels of deiminated histones were detected in neutrophils from RA patients. CONCLUSION Circulating autoantibodies in FS are preferentially directed against PAD-4-deiminated histones and bind to activated neutrophils and NETs. Thus, increased reactivity with modified autoantigens in FS implies a direct contribution of neutrophil activation and the production of NET-associated nuclear autoantigens in the initiation or progression of FS.

Pathogenesis of systemic sclerosis

Systemic scleroderma (SSc) is one of the most complex systemic autoimmune diseases. It targets the vasculature, connective tissue-producing cells (namely fibroblasts/myofibroblasts), and components of the innate and adaptive immune systems. Clinical and pathologic manifestations of SSc are the result of: (1) innate/adaptive immune system abnormalities leading to production of autoantibodies and cell-mediated autoimmunity, (2) microvascular endothelial cell/small vessel fibroproliferative vasculopathy, and (3) fibroblast dysfunction generating excessive accumulation of collagen and other matrix components in skin and internal organs. All three of these processes interact and affect each other. The disease is heterogeneous in its clinical presentation that likely reflects different genetic or triggering factor (i.e., infection or environmental toxin) influences on the immune system, vasculature, and connective tissue cells. The roles played by other ubiquitous molecular entities (such as lysophospholipids, endocannabinoids, and their diverse receptors and vitamin D) in influencing the immune system, vasculature, and connective tissue cells are just beginning to be realized and studied and may provide insights into new therapeutic approaches to treat SSc.

Vascular involvement in systemic sclerosis (scleroderma)

Systemic sclerosis (SSc) is an acquired multiorgan connective tissue disease with variable mortality and morbidity dictated by clinical subset type. The etiology of the basic disease and pathogenesis of the systemic autoimmunity, fibrosis, and fibroproliferative vasculopathy are unknown and debated. In this review, the spectrum of vascular abnormalities and the options currently available to treat the vascular manifestations of SSc are discussed. Also discussed is how the hallmark pathologies (ie, how autoimmunity, vasculopathy, and fibrosis of the disease) might be effected and interconnected with modulatory input from lysophospholipids, sphingosine 1-phosphate, and lysophosphatidic acid.

Lupus-like nephritis in an HIV-positive patient: report of a case and review of the literature.

The most common manifestation of HIV/AIDS in the kidney is the collapsing variant of focal segmental glomerular sclerosis, HIV-associated nephropathy (HIVAN). Other forms of renal disease in HIV-infected patients include mesangial proliferative glomerulonephritis (GN), membranoproliferative GN, IgA nephropathy, minimal change disease and proliferative immune-complex GN. We present the case of a 42-year-old Caucasian male with HIV infection, treatment associated peripheral neuropathy, nephrotic syndrome and progressive renal failure. The initial and subsequent kidney biopsies showed diffuse proliferative glomerulonephritis resembling diffuse proliferative (WHO class IV) lupus nephritis. There was no clinical or serological evidence of systemic lupus erythematosus (SLE). Proteinuria improved with ACE-inhibitors, and renal function remained relatively stable while receiving highly active antiretroviral therapy (HAART). A precipitous decline in renal function to end-stage renal disease followed a brief period of withdrawal from potent antiretroviral therapy during which the viral load rebounded. Considering previously reported cases, it appears that lupus-like nephritis is a rare but well-defined pattern of immune-complex-induced renal injury seen in HIV-infected patients. It appears to be markedly responsive to HAART.

Signal recognition antibody-positive myopathy and response to intravenous immunoglobulin G (IVIG)

S ignal recognition particle (SRP) antibody is present in 4% to 6% of patients with idiopathic inflammatory myopathies. Signal recognition particle antibody positivity is associated with severe myopathy, high creatine phosphokinase (CPK) levels, muscle necrosis with little inflammation, and poor response to traditional treatment. We report a patient with refractory SRPpositive myopathy who responded to intravenous immunoglobulin (IVIG) therapy. A 44-year-old Hispanic man presented with progressive proximal weakness for 2 months and an elevated serum CPK of 17,209 U/L (reference range, 22Y269 U/L). Physical examination revealed symmetrical Medical Research Council (MRC) 2/5 proximal strength of the upperand lower-limb girdle. The remainder of the examination including motor reflex testing, cranial nerve and sensory testing, and dermatological examination were within normal limits. Computed tomography scan of the chest, abdomen, and pelvis showed no evidence for malignancy. Laboratory workup, including HIV, thyroid-stimulating hormone, Jo-1 antibody, anti-Smith antibody, anti-RNP antibody, and hepatitis A, B, and C panels, was negative. Chest radiograph did not show abnormalities. A muscle biopsy revealed an active necrotizing myopathy with fiber atrophy, necrosis, phagocytosis, and some regenerating fibers with minimal inflammation (Figs. 1A and B), with only rare scattered CD45-positive lymphocytes (Fig. 2) that appeared to be of CD4 origin. CD45 is an antibody stain that recognizes hematopoietic lineage cells except for red cells. It is a nonselective lymphocyte stain that is used to recognize inflammation. There were frequent macrophages in the interstitial area (Fig. 3). Only rare vessels were noted to stain positive for C5b-9 (complement membrane attack complex) (Fig. 4). Therapy with prednisone (1 mg/kg per day) was initiated. However, the weakness continued, and 3 months later he was given 1 g/kg of IVIG in 2 divided doses. The CPK decreased by approximately 50%, and there was normalization of the muscle strength. However, because the CPK levels remained elevated, additional treatment with disease-modifying antirheumatic drugs (DMARDs), including azathioprine, was given with limited success (Table, Fig. 5). A repeat muscle biopsy obtained 2 years later was unchanged. Subsequent treatment with methotrexate and leflunomide was not successful (Table, Fig. 5). In March 2011, he presented with increasing muscle weakness, an elevated CPK of 6566 U/L and 2/5 motor strength in the proximal upper and lower extremities bilaterally. Signal recognition particle antibody, which was determined by line immunoassay from Immco (Buffalo, NY), was positive. In view of his partial earlier response to IVIG and reports of successful treatment of inflammatory myopathies with this agent given monthly for 4 months to 6 months, IVIG was administered (1 g/kg in 2 divided doses). His muscle strength improved to MRC 4/5 of the upperand lower-limb girdle 1 month following his first dose of IVIG, and his CPK normalized to 149 U/L. He received monthly infusions of IVIG for the following 2 months (dose range, 1Y2 g/kg) with continued normal CPK levels (168 U/L) and normal muscle strength testing. However, he missed his fourth monthly infusion of IVIG, and the following month he was found to have an elevation of the CPK to 989 U/L, although muscle strength testing remained normal. He received his fourth dose of IVIG, and his CPK decreased again to normal (193U/L). Over the course of treatment with IVIG, his prednisone was tapered to 0.5 mg/kg per day, a significant decrease compared with doses before IVIG treatment (Fig. 5). The patient did not return for clinic follow-up for 5 months following this last IVIG treatment. He returned to clinic follow-up in April 2012, with complaints of weakness for 10 days, which started when he had run out of his prednisone. On examination, muscle strength testing was MRC 4/5 of the upperand lower-limb girdle, and CPK was elevated at 3038 U/L. He was given an additional course of IVIG, with resolution of weakness and normalization of the CPK. Current plans are for monthly follow-up with clinical determination for frequency of IVIG infusions and tapering of prednisone.

Breast Lymphoma Complicating Anti–Tumor Necrosis Factor Therapy in Rheumatoid Arthritis

The relationship between anti-TNF therapy and development of lymphoma in Rheumatoid arthritis (RA) patients is controversial. However lymphomas of unusual types and sites have been reported among RA patients receiving anti-TNF therapy. Primary lymphoma of the breast is a rare entity and has never been reported to occur among RA patients taking anti-TNF therapy. This is the first case of primary lymphoma of the breast reported among RA patients on anti-TNF therapy. Rheumatoid arthritis patients currently on anti-TNF therapy should undergo routine gynecological examination.

Aspirin sensitivity and coronary artery disease: implications for the practicing cardiologist

Aspirin is the most commonly used antiplatelet agent in patients with coronary artery disease (CAD). It continues to play a key role as an antiplatelet agent given its long-term safety, efficacy and low cost. Aspirin or NSAID hypersensitivity is not an uncommon occurrence and can vary from generalized urticaria and angioedema to exacerbation of upper and lower respiratory tract reactions. It is not uncommon for clinicians to avoid using aspirin and alternative agents when encountering aspirin hypersensitivity among CAD patients. However, given the critical role of aspirin in CAD patients, particularly among those who receive the drug-eluting stents, aspirin desensitization can be useful. This article highlights the importance of aspirin desensitization, the mechanism and the process involved. We draw attention to recently described rapid desensitization protocols and how they can be more useful than the old procedure.

Screening and treatment of latent tuberculosis among patients receiving biologic agents, a national and international survey of rheumatologists

Objective We sought to understand the current practice patterns of both US and international members of the American College of Rheumatology (ACR) in this regard. Methods A set of questionnaires developed by a focus group of faculties and fellows of the Rheumatology Division of University of Tennessee Health Science Center, Memphis, TN, was sent electronically using an online survey tool to 4433 rheumatologists who are ACR members in the United States and internationally. Results Seven hundred sixty-eight physicians out of 4433 ACR members responded to the electronic survey, with a response rate of 17.32%. The preferred screening method by most of the respondents was either tuberculin skin test (19%) or interferon &ggr; release assay (32%) or both. For treatment of latent tuberculosis infection (LTBI) overall, 49% of the respondents would refer management to infectious disease specialist or the health department, 37% would initiate isoniazid for 9 or 12 months, and 14% would use isoniazid for 6 months. Approximately 60% of respondents would initiate anti–tumor necrosis factor therapy after being on LTBI treatment for 1 month. The other respondents were almost equally divided among the 3 responses: 2, 3, 6, or 9 months. Conclusions There is a large disagreement regarding the method used and how often to screen for LTBI after initiating biologic therapy and how soon biologic treatment would be started after initiating LTBI therapy. Another disagreement exists regarding the duration of LTBI therapy. The information obtained from the survey can be taken into account when ACR or other international member organizations formulate future recommendations regarding screening and treatment of LTBI.

Rheumatoid arthritis and periodontal disease: What are the similarities and differences?

Rheumatoid arthritis (RA) and periodontal disease (PD) are chronic inflammatory diseases that share similar osteoclasia, human leukocyte antigen‐DR4 allelic genes and immunological profile, and characteristic cytokines. Smoking can contribute to more severe RA and PD; secretion of pro‐inflammatory mediators destroys the soft synovial membrane and periodontium, respectively. Anti‐citrullinated protein antibodies and anti‐α‐enolase antibody are characteristic of these two diseases. Some studies suggest that PD may be associated with RA. Anti‐Porphyromonas gingivalis (P. gingivalis) antibody, but no P. gingivalis bacterium can be detected in RA patients’ joint fluid. Anti‐P. gingivalis antibody has been seen as a biomarker of RA. Both diseases share some nosogenesis and common pathological pathways. However, there are differing views on the connection between the two diseases. Interferon‐inducible‐16 (IFI16) is a genic marker of RA; moreover, the association between IFI16 and PD is rare. Some studies suggest PD is related to periodontal parameters and patients pathological status rather than RA. Disease frequency in men and women differ between these two diseases. The expression of interleukin‐17 (IL‐17) receptor only associates with different genders in PD (PD of different sexes have different IL‐17 expressions). Periodontal local treatment only affects clinical periodontal status, and it does not alter circulating levels of IL‐6, tumor necrosis factor‐alpha or C‐reactive protein which are associated with RA. This review examines the similarities and differences between these two diseases and explores possible interactions. Importantly, we will discuss whether PD is a feature of RA and whether this knowledge provides helpful information in future treatment of both diseases.

Adherence and systemic reaction rates to allergy immunotherapy among veterans.

Background Although allergen immunotherapy (AIT) is effective and safe, nonadherence is common. Limited data exist regarding adherence to ATT, factors that affect adherence, and systemic reactions associated with ATT among veteran populations. Objective To evaluate adherence to AIT and the prevalence of reactions secondary to AIT among patients at the Veterans Affairs Medical Center, Memphis, Tennessee. Methods A retrospective chart review was performed of veterans who received AIT at a single Veterans Affairs facility. Age, race, sex, the total number of shots, travel distance, a diagnosis of posttraumatic stress disorder (PTSD), and the number of severe adverse reactions were compared between the veterans who were adherent and veterans who were nonadherent. Results The overall adherence rate was 60.9%. Factors associated with adherence were a chart diagnosis of PTSD (293% [adherent group] versus 13.6% [nonadherent group]; p = 0.03) and home residence being a further distance from the facility (21.9 miles / 35.2 kilometers [adherent group] versus 18.0 miles/28.9 kilometers [nonadherentgroup]; p = 0.03). Patients who were adherent received an average of more total injections compared with patients who were nonadherent. Age, sex, race, and history of systemic reactions during AIT displayed no statistically significant differences between the groups. There were a total of 20 systemic reactions, and the systemic reaction rate was 0.2% per AIT encounter and 0.1% per injection. Conclusion AIT adherence and systemic reaction rates among veterans at our facility was comparable with similar studies. Adherence was associated with a chart diagnosis of PTSD and home residence that was further away from the clinic.