Rheumatoid Arthritis: Fox RI

Fox RI. · No affiliation provided · Arthritis Rheum. · Pubmed #11762679 No free full text.

This publication has no abstract.

Fox RI, Liu AY. · Rheumatology Clinic Scripps Memorial Hospital and Research Foundation, La Jolla, CA 92037, USA. · Clin Dermatol. · Pubmed #16966020 No free full text.

Abstract: Sjogren's Syndrome (SS) is a systemic autoimmune disease characterized by dry eyes (keratoconjunctivis sicca) and dry mouth (xerostomia). To fulfill diagnostic criteria, patients must have objective signs of dryness on examination and laboratory confirmation of an autoimmune process as evidenced by a positive autoantibody to SS-A antigen or a characteristic lip biopsy. SS may exist as a primary condition or in association with other systemic autoimmune disorders (termed secondary SS) such as rheumatoid arthritis, systemic lupus erythematous (SLE), progressive systemic sclerosis (scleroderma), or dermatomyositis. Exclusions to the diagnosis include pre-existing lymphoma, hepatitis C or HIV infection. Pathogenesis involves both genetic (especially HLA-DR) and environmental factors. Both T-cells and B-cells are involved in the generation of cytokines and chemokines within the glands. The epithelial cells of the glands also play a role in pathogenesis. The dermatologic manifestations range from drynessness (sicca) and its complications to vasculitis. There is a significant overlap in the clinical manifestations, as well as treatment, of SS and SLE. However, SS patients require special attention to the complications of ocular dryness (keratocojunctivitis sicca and blepharitis) and oral dryness (rapid tooth loss and oral candidiasis) SS patients have a markedly increased risk of lymphoma and enlarged lymph nodes or persistently enlarged parotid/submandibular glands that require further evaluation.

Fox RI. · Rheumatology Clinic, Scripps Memorial Hospital and Research Foundation, La Jolla, CA 92037, USA. · Lancet. · Pubmed #16039337 No free full text.

Abstract: Sjögren's syndrome is a chronic autoimmune disorder of the exocrine glands with associated lymphocytic infiltrates of the affected glands. Dryness of the mouth and eyes results from involvement of the salivary and lacrimal glands. The accessibility of these glands to biopsy enables study of the molecular biology of a tissue-specific autoimmune process. The exocrinopathy can be encountered alone (primary Sjögren's syndrome) or in the presence of another autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosus, or progressive systemic sclerosis. A new international consensus for diagnosis requires objective signs and symptoms of dryness including a characteristic appearance of a biopsy sample from a minor salivary gland or autoantibody such as anti-SS-A. Exclusions to the diagnosis include infections with HIV, human T-lymphotropic virus type I, or hepatitis C virus. Therapy includes topical agents to improve moisture and decrease inflammation. Systemic therapy includes steroidal and non-steroidal anti-inflammatory agents, disease-modifying agents, and cytotoxic agents to address the extraglandular manifestations involving skin, lung, heart, kidneys, and nervous system (peripheral and central) and haematological and lymphoproliferative disorders. The most difficult challenge in diagnosis and therapy is patients with symptoms of fibromyalgia (arthralgia, myalgia, fatigue) and oral and ocular dryness in the presence of circulating antinuclear antibodies.

Fox RI. · Allergy and Rheumatology Clinic, Scripps Memorial Hospital and Research Foundation, La Jolla, California, USA. · Adv Exp Med Biol. · Pubmed #12614037 No free full text.

This publication has no abstract.

Fox RI. · Rheumatology Clinic, Scripps Memorial Hospital and Research Foundation, 9850 Genesee Ave., #910, La Jolla, CA 92037, USA. · Expert Opin Investig Drugs. · Pubmed #12556218 No free full text.

Abstract: Sjogren's syndrome (keratoconjunctivis sicca) is a relatively common disorder with incidence of approximately 0.5% of adult women. It has both local (ocular and oral) features as well as systemic manifestations. There has been recent FDA approval of agents to stimulate salivation (pilocarpine and cevimeline) and studies are in progress to determine their role in the treatment of dry eye. New therapies are in clinical trials for ocular manifestations with the most interest focused on topical cyclosporin A and purinogenic receptor agonists. In oral therapy, topical human interferon has reported encouraging results in short-term studies. However, the high placebo response (probably reflecting the beneficial response of mechanical stimulation of the buccal mucosa by the lozenge) and the response to much cheaper therapies (such as acid maltose lozenges) may offer safer and cheaper alternatives. For systemic disease, there is interest in tumour necrosis factor inhibitors. However, the cost-effectiveness and safety of biological agents needs longer term follow up, as they appear much less dramatic in their effect on systemic lupus erythematosus or Sjogren's syndrome than in rheumatoid arthritis.

Fox RI, Stern M. · Allergy and Rheumatology Clinic, Scripps Memorial Hospital and Research Foundation, La Jolla, CA 92037, USA. · Scand J Rheumatol Suppl. · Pubmed #12109541 No free full text.

Abstract: Although biopsies of salivary and lacrimal glands from patients with Sjögren's syndrome (SS) have focal lymphocytic infiltrates and partial destruction of glandular secretory units (acinar and ductal structures), the degree of dryness is beyond that expected for the level of glandular destruction. The failure to exhibit adequate secretory function is not due simply to the destruction of neural innervation to the residual glandular elements or the absence of receptors for acetylcholine on the glandular cells. It is likely that release of cytokines by lymphocytes and glandular cells (especially interleukin-1, interleukin-6 and tumor necrosis factor alpha), autoantibodies and metalloproteinases lead to decreased release of neurotransmitters and decreased response of the residual glandular cells to available neurotransmitters. The ability to modulate immune response and stimulate residual glandular elements provides new therapeutic opportunities for Sjögren's patients.

Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, Talal N, Weisman MH, Anonymous00126. · Department of Internal Medicine and Rheumatology, Ospedale Villamaria, Piombino, LI, Italy. · Ann Rheum Dis. · Pubmed #12006334 links to  free full text

Abstract: Classification criteria for Sjögren's syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.

Fox RI, Konttinen Y, Fisher A. · Allergy and Rheumatology Clinic, Scripps Memorial Hospital and Research Foundation, La Jolla, California 92037, USA. · Clin Immunol. · Pubmed #11726216 No free full text.

Abstract: Two muscarinic agonists (pilocarpine and cevimeline) have recently been approved for the treatment of symptoms of xerostomia in Sjögren's syndrome (SS). These agents stimulate the M1 and M3 receptors present on salivary glands, leading to increased secretory function. The use of these agents emphasizes the importance of neuroendocrine mechanisms in SS, which is considered an autoimmune disorder. We review recent studies on the release of cytokines and metalloproteinases in SS-affected glands and their influence on the release of and response to neurotransmitters. Also, we review the structure and function of muscarinic receptors as they may relate to SS and the potential use of novel muscarinic agonists in SS.

Fox RI, Michelson P, Casiano CA, Hayashi J, Stern M. · Allergy and Rheumatology Clinic, Scripps Memorial Hospital and Research Foundation, La Jolla, California 92037, USA. · Clin Dermatol. · Pubmed #11134854 No free full text.

This publication has no abstract.

Fox RI, Michelson P. · Allergy and Rheumatology Clinic and the Division of Ophthalmology, Scripps Memorial Hospital, La Jolla, CA, USA. · J Rheumatol Suppl. · Pubmed #11128699 No free full text.

Abstract: Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by complaints of sicca symptoms (dry eye and mouth) and can be associated with other autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis, etc). As a result, SS can be difficult to diagnose. Currently, there are several criteria standards for SS, including the San Diego criteria and the European Study Group criteria. According to the San Diego criteria, the incidence of SS is about 0.5%, whereas for the European Study Group it ranges from 3% to 5%. This almost 10-fold difference in SS incidence has led to confusion for both the clinician and researcher. The tearing reflex involves a neural loop in which afferent nerve signals from the ocular surface are relayed centrally to the medulla. The input from the afferent nerves is then processed and sent back via efferent nerves stimulating blood vessels and secretory glands to provide and pump water for tears. Immune factors, such as cytokines, have a profound effect on the tearing mechanism by damaging secretory glands and releasing antibodies to influence the response of muscarinic M3 receptors. Thus, the interaction of neural and immune factors affects the secretory response of glands and contributes to the pathogenesis of SS sicca symptoms. The recent development of muscarinic agonists, such as pilocarpine and cevimeline, serves an important step in recognizing the interaction between the immune and neuroendocrine systems.

Fox RI. · Allergy and Rheumatology Clinic, Scripps Institute for Medical Research, 9850 Genesee Avenue, #860, La Jolla, CA 92037, USA. · Expert Opin Investig Drugs. · Pubmed #11060789 No free full text.

Abstract: Sjögren's syndrome (SS) is a systematic autoimmune disease characterised by dysfunction of the lacrimal and salivary glands. This dryness leads to the symptoms of dry eyes and keratoconjunctivitis sicca, which is painful and may predispose patients to ocular infections. Also, SS patients develop dry mouth, which is uncomfortable and associated with progressive dental disease. SS is divided into secondary SS (where the dryness symptoms are associated with another well defined autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosus, or scleroderma) and primary SS (where the patients do not fulfil criteria for another well defined associated autoimmune disease). Primary SS has extra glandular organ involvement including lung (interstitial pneumonitis), renal (interstitial nephritis), peripheral and central nervous system manifestations, vasculitis of skin and other organs and increased frequency of lymphoma. This review will concentrate on primary SS. Therapies are divided into agents for topical replacement of deficient secretions (artificial tears, artificial salivas), stimulation of muscarinic M3 receptors (pilocarpine, cevimeline) to increase aqueous secretions, reduction of topical inflammation (topical cyclosporin or corticosteroids for the eye and fluorides or antibacterial varnishes for the mouth) and modification of the immune response in a manner similar to treatment of systemic lupus (antimalarial drugs, methotrexate, cyclophosphamide and perhaps newer agents such as leflunomide or TNF inhibitors).

Fox RI, Stern M, Michelson P. · Allergy and Rheumatology Clinic, Scripps Memorial Hospital and Research Foundation, La Jolla, California 92037, USA. · Curr Opin Rheumatol. · Pubmed #10990175 No free full text.

Abstract: Sjögren syndrome (SS), the second most common autoimmune rheumatic disease, refers to keratoconjunctivitis sicca and xerostomia resulting from immune lymphocytes that infiltrate the lacrimal and salivary glands. However, differential diagnosis remains confusing due to the high prevalence of vague symptoms of dryness, fatigue, and myalgias in the general population. The problems of diagnosis are further compounded by the finding of "positive" antinuclear antibodies in a high percent of the general population. Unless minor salivary gland biopsies are read by experienced observers, nonspecific changes of sialadenitis are frequently confused with the focal lymphocytic infiltrates that are characteristic of SS. The distinction between fibromyalgia patients with low titer antinuclear antibodies and primary SS remains difficult. Even in patients fulfilling strict criteria for SS, the genomic search for critical genes has proven difficult due to the multigenic pattern of inheritance and strong role of currently undefined environmental factors. No single environmental factor has been detected in the majority of SS patients. SS-like syndrome has been detected in certain patients with HTLV-1 and hepatitis C infection, providing clues to pathogenesis. Even in SS patients with marked sicca symptoms, minor salivary gland biopsy shows that almost 50% of glandular cells are still detected on biopsy. These results imply the importance of immune factors such as cytokines and autoantibodies in decreasing neuro-secretory circuits and induction of glandular dysfunction. Of potential importance, an antibody against muscarinic M3 receptor that can decrease secretory function when injected into rodents is frequently found in the sera of SS patients. Newly developed topical and oral therapies can ease the oral and ocular dryness. Orally administered agonists of the muscarinic M3 receptor (pilocarpine and cevimeline) have recently been approved by the US Food and Drug Administration to increase salivary secretion. Topical ocular use of low-dose corticosteroids or cyclosporin may decrease conjunctival surface inflammation. In a Phase II double-blind study, orally administered interferon alpha (150 U) led to improved saliva flow and symptoms. In pregnant patients with evidence of fetal distress, oral dexamethasone is preferred because this agent crosses the placenta effectively. In animal models, antagonists of tumor necrosis factor and inhibitors of de novo pyrimidine synthesis appear promising.

Fox RI, Herrmann ML, Frangou CG, Wahl GM, Morris RE, Strand V, Kirschbaum BJ. · Division of Rheumatology, Scripps Memorial and Research Institutes, La Jolla, California 92037, USA. · Clin Immunol. · Pubmed #10600330 No free full text.

Abstract: Leflunomide (Arava) has recently been approved by the Food and Drug Administration for the treatment of rheumatoid arthritis (RA). This approval was based on data from a double-blind, multicenter trials in the United States (leflunomide versus methotrexate versus placebo) in which leflunomide was superior to placebo and similar to methotrexate (Strand et al., Arch. Intern. Med., in press, 1999). In a multicenter European trial, leflunomide was similar to sulfasalazine in efficacy and side effects (Smolen et al., Lancet 353, 259-266, 1999). Both methotrexate and leflunomide retarded the rate of radiolographic progression, entitling them to qualify as disease-modifying agents (Strand et al., Arch. Intern. Med., in press, 1999). Leflunomide is an immunomodulatory drug that may exert its effects by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which plays a key role in the de novo synthesis of the pyrimidine ribonucleotide uridine monophosphate (rUMP). The inhibition of human DHODH by A77 1726, the active metabolite of leflunomide, occurs at levels (approximately 600 nM) that are achieved during treatment of RA. We propose that leflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with the cell cycle progression due to inadequate production of rUMP and utilizing mechanisms involving p53. The relative lack of toxicity of A77 1726 on nonlymphoid cells may be due to the ability of these cells to fulfill their ribonucleotide requirements by use of salvage pyrimidine pathway, which makes them less dependent on de novo synthesis.

Fox RI, Tornwall J, Michelson P. · Scripps Memorial Hospital, Allergy and Rheumatology Clinic, La Jolla, California 92037, USA. · Curr Opin Rheumatol. · Pubmed #10503656 No free full text.

Abstract: Modification of the European Cooperative Group (EEC) criteria for Sjögren's Syndrome (SS) should lead to less confusion in diagnosis and therapeutic trials. The proposed EEC modification will require either a positive minor salivary gland biopsy or a positive autoantibody against Sjögren's-associated A (Ro) or B (La) antigen. This modification will decrease the proportion of women fulfilling EEC criteria from 3-5% to about 0.5%, which is similar to San Diego and San Francisco criteria. Genetic studies have shown increased frequency of alleles for peptide transporter genes TAP1 (0101) and TAP2 (0101) genes as well as tumor necrosis factor microsatellite a2 alleles. Although these markers confer markedly increased risk, they are found in only a small proportion of patients. An increased frequency of drug (antibiotic) allergy and other allergic manifestations appears present in patients with SS and may be linked to HLA-DR3. Hepatitis C as a cause of sicca symptoms, positive anti-nuclear autoantibodies, and mixed cryoglobulinemia is increasingly reported in different parts of the world. Antibodies against muscarinic M3 receptor and expression of costimulatory molecules (CD80 and CD86) by ductal epithelial cells may play a role in pathogenesis. Treatment with pilocarpine is effective in double-blind trials and low dose oral alpha interferon looks promising in initial open studies. In pregnant patients who exhibit evidence of neonatal heart block, treatment with dexamethasone is preferred over prednisone, since the placenta is unable to metabolically activate the latter compound.

Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, Jackson CG, Lange M, Burge DJ. · Brigham and Women's Hospital, Boston, MA 02115, USA. · N Engl J Med. · Pubmed #9920948 links to  free full text

Abstract: BACKGROUND: Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease. This study was undertaken to determine whether the addition of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein (TNFR:Fc), to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate. METHODS: In a 24-week, double-blind trial, we randomly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week (or as low as 10 mg per week for patients unable to tolerate higher doses) to receive either etanercept (25 mg) or placebo subcutaneously twice weekly while continuing to receive methotrexate. The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity (ACR 20) at 24 weeks. RESULTS: The addition of etanercept to methotrexate therapy resulted in rapid and sustained improvement. At 24 weeks, 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria (P<0.001); 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria (for a 50 percent improvement) (P<0.001). Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity. The only adverse events associated with etanercept were mild injection-site reactions, and no patient withdrew from the study because of adverse events associated with etanercept. CONCLUSIONS: In patients with persistently active rheumatoid arthritis, the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone.

Fox RI, Herrmann ML, Frangou CG, Wahl GM, Morris RE, Kirschbaum BJ. · Division of Rheumatology, Scripps Memorial and Research Institutes, La Jolla, California, USA. · BioDrugs. · Pubmed #18031184 No free full text.

Abstract: Leflunomide has recently been approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis. This approval was based on data from double-blind multicentre trials in the US (US 301; leflunomide versus methotrexate versus placebo) and multicentre European trials (leflunomide versus sulfasalazine versus placebo, and leflunomide versus methotrexate versus placebo). In these trials, leflunomide was superior to placebo and similar to methotrexate or sulfasalazine in efficacy and adverse effects. Both methotrexate and leflunomide retarded the rate of radiological progression, entitling them to qualify as disease-modifying agents (DMARDs). Leflunomide is an immunomodulatory drug that may exert its effects by inhibiting the mitochondrial enzyme dihydro-orotate dehydrogenase (DHO-DH), which plays a key role in the de novo synthesis of the pyrimidine ribonucleotide uridine monophosphate (rUMP). The inhibition of human DHO-DH by A77-1726, the active metabolite of leflunomide, occurs at concentrations (approximately 600 nmol/L) that are achieved during treatment of rheumatoid arthritis. We propose that leflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with cell cycle progression. This is mediated by inadequate production of rUMP and utilises mechanisms involving the sensor protein p53. The relative lack of toxicity of A77-1726 on nonlymphoid cells may be due to the ability of these cells to fulfil their ribonucleotide requirements by use of the salvage pyrimidine pathway, which makes them less dependent on de novo synthesis.

Maruyama T, Saito I, Hayashi Y, Kompfner E, Fox RI, Burton DR, Ditzel HJ. · Department of Immunology, The Scripps Research Institute, La Jolla, California, USA. · Am J Pathol. · Pubmed #15215161 links to  free full text

Abstract: Lymphocyte infiltration of salivary and lacrimal glands leading to diminished secretion and gland destruction as a result of apoptosis is thought to be pivotal in the pathogenesis of Sjögren's syndrome (SS). The cytoskeletal protein alpha-fodrin is cleaved during this apoptotic process, and a strong antibody (Ab) response is elicited to a 120-kd fragment of cleaved alpha-fodrin in the majority of SS patients, but generally not in other diseases in which apoptosis also occurs. Little is known about the anti-alpha-fodrin autoantibody response on a molecular level. To address this issue, IgG phage display libraries were generated from the bone marrow of two SS donors and a panel of anti-alpha-fodrin IgGs was isolated by selection on alpha-fodrin immunoblots. All of the human monoclonal Abs (hmAbs) reacted with a 150-kd fragment and not with the 120-kd fragment or intact alpha-fodrin, indicating that the epitope recognized became exposed after alpha-fodrin cleavage. Analysis of a large panel of SS patients (defined by the strict San Diego diagnostic criteria) showed that 25% of SS sera exhibited this 150-kd alpha-fodrin specificity. The hmAbs stained human cultured salivary acinar cells and the staining was redistributed to surface blebs during apoptosis. They also stained inflamed acinar/ductal epithelial cells in SS salivary tissue biopsies, and only partially co-localized with monoclonal Abs recognizing the full-length alpha-fodrin. Our study shows that in SS patients, neoepitopes on the 150-kd cleaved product of alpha-fodrin become exposed to the immune system, frequently eliciting anti-150-kd alpha-fodrin Abs in addition to the previously reported anti-120-kd Abs. The anti-150-kd alpha-fodrin hmAbs may serve as valuable reagents for the study of SS pathogenesis and diagnostic analyses of SS salivary gland tissue.

Fox RI, Morgan SL, Smith HT, Robbins BA, Choc MG, Baggott JE. · Division of Rheumatology, Scripps Memorial Hospital and Research Foundation, La Jolla, California, USA. · Rheumatology (Oxford). · Pubmed #12730515 links to  free full text

Abstract: OBJECTIVE: To study the pharmacokinetics of methotrexate (MTX) plus cyclosporin A (CSA) in patients with rheumatoid arthritis (RA). METHODS: On day 1 of the study, patients with RA receiving stable doses of MTX had blood and urine levels of MTX and its metabolite 7-hydroxymethotrexate (7-OH-MTX) measured post oral dosing of the drug. MTX was then discontinued and CSA therapy was started on day 8. On day 20, blood levels of CSA and CSA metabolites were measured post drug dosing. On day 23, MTX therapy was restarted and levels of MTX, CSA and their metabolites were again measured as described above. RESULTS: In the 30 patients, coadministration of CSA and MTX led to a 26% increase in mean peak plasma MTX concentration (P < 0.01), an 18% increase in the mean plasma MTX concentration area under the curve (AUC, P=0.01) and an 80% decrease in plasma 7-OH-MTX AUC (P < 0.01). In 13 patients receiving a 10 mg MTX dose, CSA reduced urinary 7-OH-MTX excretion by 87% (P < 0.01) without altering MTX excretion. MTX did not alter the pharmacokinetics of CSA or its metabolites. CONCLUSION: CSA may block oxidation of MTX to its relatively inactive metabolite, 7-OH-MTX, thereby potentiating MTX efficacy.

Storgard CM, Stupack DG, Jonczyk A, Goodman SL, Fox RI, Cheresh DA. · Departments of Immunology and Vascular Biology (IMM24), The Scripps Research Institute, La Jolla, California 92037, USA. · J Clin Invest. · Pubmed #9884333 links to  free full text

Abstract: Rheumatoid arthritis (RA) is an inflammatory disease associated with intense angiogenesis and vascular expression of integrin alphavbeta3. Intra-articular administration of a cyclic peptide antagonist of integrin alphavbeta3 to rabbits with antigen-induced arthritis early in disease resulted in inhibition of synovial angiogenesis and reduced synovial cell infiltrate, pannus formation, and cartilage erosions. These effects were not associated with lymphopenia or impairment of leukocyte function. Furthermore, when administered in chronic, preexisting disease, the alphavbeta3 antagonist effectively diminished arthritis severity and was associated with a quantitative increase in apoptosis of the angiogenic blood vessels. Therefore, angiogenesis appears to be a central factor in the initiation and persistence of arthritic disease, and antagonists of integrin alphavbeta3 may represent a novel therapeutic strategy for RA.