Daniel G. Arkfeld

Differential MHC Class II-Mediated Presentation of Rheumatoid Arthritis Autoantigens by Human Dendritic Cells and Macrophages

Rheumatoid arthritis is characterized by synovial joint infiltration of activated CD4+ T cells and MHC class II+ APC, and is linked to specific HLA-DR alleles. Candidate autoantigens in synovial fluid and cartilage include type II collagen (CII) and cartilage gp39 (HCgp39). Using preparations of native Ag and T cells derived from Ag-immunized DR4-transgenic mice, we determined that human ex vivo differentiated DR4+ dendritic cells (DC) and macrophages (Mφ) can mediate MHC class II presentation of CII or HCgp39 epitopes. The form of the Ag (soluble, partially degraded, or particulate) delivered to the APC influenced its presentation by DC and Mφ. DC efficiently presented partially degraded, but not native CII α-chains, while Mφ presentation was most efficient after phagocytosis of bead-conjugated CII. Both DC and Mφ presented soluble HCgp39, and activated Mφ from some donors presented epitopes derived from endogenously synthesized HCgp39. When synovial fluid from rheumatoid arthritis patients was used as a source of Ag, DC presentation of HCgp39 and CII epitopes was efficient, indicating that synovial fluid contains soluble forms of CII and HCgp39 amenable to internalization, processing, and presentation. These data support the hypothesis that CII and HCgp39 are autoantigens and that their class II-mediated presentation by DC and Mφ to T cells in vivo has a critical role in the pathogenesis of human rheumatoid arthritis.

The potential utility of B cell-directed biologic therapy in autoimmune diseases

Increasing awareness of the importance of aberrant B cell regulation in autoimmunity has driven the clinical development of novel B cell-directed biologic therapies with the potential to treat a range of autoimmune disorders. The first of these drugs—rituximab, a chimeric monoclonal antibody against the B cell-specific surface marker CD20—was recently approved for treating rheumatoid arthritis in patients with an inadequate response to other biologic therapies. The aim of this review is to discuss the potential use of rituximab in the management of other autoimmune disorders. Results from early phase clinical trials indicate that rituximab may provide clinical benefit in systemic lupus erythematosus, Sjögren’s syndrome, vasculitis, and thrombocytopenic purpura. Numerous case reports and several small pilot studies have also been published reporting the use of rituximab in conditions such as myositis, antiphospholipid syndrome, Still’s disease, and multiple sclerosis. In general, the results from these preliminary studies encourage further testing of rituximab therapy in formalized clinical trials. Based on results published to date, it is concluded that rituximab, together with other B cell-directed therapies currently under clinical development, is likely to provide an important new treatment option for a number of these difficult-to-treat autoimmune disorders.

Infliximab treatment of Familial Mediterranean fever and its effect on secondary AA amyloidosis.

We describe a patient with a long history of familial Mediterranean fever who developed proteinuria as a result of secondary AA amyloidosis. In this patient, the inflammatory process, including recurrent attacks of arthritis, abdominal pain, nephrotic syndrome secondary to amyloidosis, and high sedimentation rate, was rapidly suppressed by treatment with infliximab and there was remarkable improvement of the proteinuria. Because TNF-&agr; is a proinflammatory cytokine that plays a major role in FMF and secondary amyloid, it is an appropriate target for therapy. Our case is the first case of reactive systemic amyloidosis secondary to familial Mediterranean fever, which responded favorably to infliximab.

Tear cathepsin S as a candidate biomarker for Sjögren's syndrome.

The diagnosis of Sjögrens syndrome (SS) in routine practice is largely a clinical one and requires a high index of suspicion by the treating physician. This great dependence on clinical judgment frequently leads to delayed diagnosis or misdiagnosis. Tear protein profiles have been proposed as simple and reliable biomarkers for the diagnosis of SS. Given that cathepsin S activity is increased in the lacrimal glands and tears of NOD mice (a murine model of SS), the aim of this study was to explore the clinical utility of using tear cathepsin S (CTSS) activity as a biomarker for SS.

Adalimumab-induced noncaseating granuloma in the bone marrow of a patient being treated for rheumatoid arthritis

Sarcoidosis is a multisystemic disease characterized by noncaseating granulomatous infiltration, primarily of the lungs and lymphatic system. While reports of the efficacy of adalimumab in the treatment of refractory sarcoidosis have been mixed, the more widely used infliximab has demonstrated clear efficacy in this disease. The association between tumor necrosis factor (TNF)-inhibitors and noncaseating granulomas in the lung has been reported in literature. With the exception of one patient treated with adalimumab, who developed pulmonary granuloma, the remaining patients described in literature were treated with etanercept. The current case study is, to our knowledge, the first to describe adalimumab-induced noncaseating granulomas in the bone marrow of a patient being treated for rheumatoid arthritis and suggests that although TNF-inhibitors are used in the treatment of granulomatous disorders, their use should be carefully monitored as, in rare cases, TNF-inhibitors may leave sufficient cytokine activation to support granuloma formation.

Treatment of multicentric reticulohistiocytosis with adalimumab, minocycline, methotrexate

Dear Editor, Multicentric reticulohistiocytosis is a rare disorder characterized by an extensive papulonodular cutaneous eruption and destructive polyarthritis. Treatment is not well known. We report a case in which a patient diagnosed with multicentric reticulohistiocytosis was successfully treated with adalimumab, methotrexate and minocycline. A 55-year-old Caucasian male was referred for treatment of multicentric reticulohistiocytosis. The patient had a 1-year history of red rash on his chest, shoulders, neck and back, with intense pruritus. Over several weeks, he developed nodules over his neck, arm extensor surfaces and on the sides and tips of his fingers. The nodules varied from several millimeters to several centimeters in diameter and were soft to firm. The patient also developed muscle aching and stiffness, which began in his shoulders and progressed to his right hand, knees and thighs, as well as swelling of his right wrist. Past medical history included Dupuytren’s contractures of both hands, which had both been surgically improved, right wrist fracture from trauma and herpes zoster of the right leg 5 years prior with resolution. Family history was negative for any connective tissue diseases. Complete blood cell count, complete general chemistry panel, erythrocyte sedimentation rate, and C-reactive protein were negative. Urinalysis was normal. Antinuclear antibody and rheumatoid factor were positive (1 : 80 and 63 U/mL, respectively), anti-cyclic citrullinated protein was negative; anti-Ro/Sjögren’s syndrome antigen A (SSA) antibodies were positive, but anti-LA/ SSB, anti-double strand DNA, anti-Smith were negative. Aldolase was low (< 7.7 mg/mL) and chest radiograph was unremarkable. Skin biopsy revealed intradermal histiocytic proliferation; most cells were mononuclear and there were no foam cells. The patient was diagnosed with multicentric reticulohistiocytosis (MRH) and was treated with methotrexate (titrated from 7.5 mg orally/week to 15 mg orally/ week over 1 month). He was also placed on etanercept (50 mg/week, subcutaneous); treatment regimen was maintained for 12 weeks. His skin lesions significantly improved. He had less joint pain, stiffness and itching, but still experienced shoulder pain and morning stiffness. The patient was placed on prednisone (5 mg orally daily), but continued to have pain. Six weeks later, etanercept was replaced with adalimumab (40 mg every 2 weeks, subcutaneous) with continuation of methotrexate (15 mg orally every week) and prednisone (5 mg orally daily). The patient improved and was completely weaned off steroids over a 2-month period; however, he continued to feel very stiff and have arthralgias, with synovitis observed in his hands and shoulders. The patient did not want to resume steroids or increase his methotrexate as he was concerned about the potential side effects. Minocycline (50 mg orally two times a day) was thus added. The patient’s cutaneous manifestations remained quiet, his arthralgias improved. He has remained on methotrexate, adalimumab and minocycline for the last 3 years. Multicentric reticulohistiocytosis is a rare disorder characterized by an extensive papulonodular cutaneous eruption and destructive polyarthritis. About 40% of patients have only joint symptoms, 30% only skin symptoms and 30% have both skin and joint symptoms. Cutaneous involvement usually occurs in an acral distribution of flesh-colored to deeply erythematous papulonodules, and takes on a typical “coral bead appearance” when involving the periungal area. Asymmetric inflammatory polyarthritis can occur. Distal interphalangeal joints are frequently involved and represent one of the clinically distinguishing features. Severe involvement of the interphalangeal joints may cause shortening and telescoping of the involved fingers, forming characteristic “opera glass hands.” The arthropathy of MRH typically rapidly progresses to destructive and erosive.

Development of Anti-CCP-positive Rheumatoid Arthritis Following Pegylated Interferon-α2a Treatment for Chronic Hepatitis C Infection

To the Editor: Interferon-α (IFN-α) is a group of cytokines with antiviral and antiproliferative effects, used for the treatment of chronic hepatitis C infection and various malignancies1. Immunomodulatory effects of IFN may lead to the induction or exacerbation of autoimmune diseases such as psoriasis, systemic lupus erythematosus, and rarely, rheumatoid arthritis (RA)1. Covalent attachment of a polyethylene glycol (PEG) moiety (pegylation) to IFN-α results in a significantly higher sustained virological response rate in patients with chronic hepatitis C compared to conventional IFN-α2. Pegylation also reduces the immunogenicity of IFN-α2. We describe the first case of a patient who developed anticyclic citrullinated peptide antibody (anti-CCP)-positive RA following treatment of chronic hepatitis C infection with pegylated IFN-α2a. A 54-year-old Chinese man with chronic hepatitis C (genotype 2a) infection was placed on a 24-week course of PEG-IFN-α2a 180 μg weekly and ribavirin 400 mg BID. His hepatitis C virus (HCV) RNA became undetectable at Week 12 … Address correspondence to Dr. Arkfeld; E-mail: arkfeld{at}usc.edu

Immune thrombocytopenia in patients with connective tissue disorders and the antiphospholipid antibody syndrome.

It has been theorized that immune thrombocytopenia (ITP) is a syndrome characterized by various defects in immune regulation, resulting in a common phenotype, decreased blood platelets, and symptoms of mucocutaneous bleeding. Most often, successful treatment of the underlying connective tissue disorder with corticosteroids or other disease-modifying agents can simultaneously improve concurrent thrombocytopenia. The best evidence to date would support the targeting of treatment to the connective tissue disorder, expecting a simultaneous improvement in the platelet count. Due to the frequent relapses associated with many of the connective tissue disorders and the frequent use of immunosuppressant agents, splenectomy should be undertaken only in highly refractory patients. Differentiating the varying immunopathic etiologies that contribute to development of connective tissue disorders may lead to a better understanding of the mechanisms of thrombocytopenia in a subset of these patients. The use of target therapies to treat connective tissue disorders has the potential of reducing the risk of the development of ITP or, conversely, inducing the development of immune thrombocytopenia.

Targeted Synovial Fluid Proteomics for Biomarker Discovery in Rheumatoid Arthritis

ObjectiveRheumatoid arthritis (RA) is an autoimmune disease that targets the synovium. The autoantigens involved in the autoantibody responses in RA are unknown. A targeted proteomics approach was used to identify proteins in RA synovial fluid (SF) that are recognized by autoantibodies in RA sera.MethodsRA SF, depleted of abundant proteins, was fractionated by two-dimensional liquid chromatography (chromatofocusing followed by reverse phase HPLC). Protein arrays constructed from these fractions were probed with RA and normal control sera, and proteins within reactive fractions were identified by mass spectrometry. The reactivity of RA sera to an identified peptide was confirmed by ELISA.ResultsRA sera specifically reacted to a SF fraction containing fibrin. Mass spectrometry analyses established the presence of a citrullinated arginine at position 271 of the fibrin fragment present in RA SF. A synthetic peptide corresponding to fibrin residues 259–287, containing the citrulline substitution at Arg 271, was recognized by 10 of 12 RA sera, but by two of 18 normal control sera and one of 10 systemic lupus erythematosus sera.ConclusionProteomics methodology can be used to directly characterize post-translational modifications in candidate autoantigens isolated from sites of disease activity. The finding that RA sera contain antibodies to the citrullinated fibrin 259–287 peptide may ultimately lead to improved diagnostic tests for RA and/or biomarkers for disease activity.

Priapism after tumor necrosis factor alpha inhibitor use

We present a possible important association of tumor necrosis factor-alpha inhibition (TNFa-i) and erectile function in a male patient with rheumatoid arthritis (RA). Long-standing, untreated RA may result in significant physical limitation and disability, however often overlooked is the association between RA and erectile and sexual dysfunction. Ischemic priapism is currently unrecognized as an adverse reaction associated with TNFa-i use and there have been no reported cases with adalimumab. Our patient, a 58-year-old Hispanic man, with sero-positive, erosive RA developed persistent priapism (17 days) despite multiple urologic interventions after initial adalimumab 40 mg administration. TNFa has recently been implicated as a potential factor in erectile dysfunction through its role in vascular reactivity. Excess TNFa, from active RA, may perturb intracavernosal smooth muscle and endothelial cell function; theoretically, TNFa inhibition may then causes excess local nitric oxide production and subsequent priapism. The potential role of TNFa-i in ED and risk for priapism is an important area for future study.