Date: Mon, 6 Jan 2003 12:52:11 -0500
Subject: [ChronicIllnessHouse] =?Windows-1252?Q?FYI_Key_Findings_in_Systemic_Lupus_Erythematosus=2C_Sj?=

Key Findings in Systemic Lupus Erythematosus, Sjögren's Syndrome, and Myositis
Robert I. Fox, MD, PhD


Key findings on systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and myositis were presented at this year's American College of Rheumatology (ACR) 66th annual meeting in New Orleans, Louisiana.

Systemic Lupus Erythematosus
In the ACR State-of-the-Art Lecture on SLE, Dr. Mark Walport[1] presented the intriguing review entitled "Understanding the Pathogenesis of SLE: The Garbage Disposal Hypothesis." It has recently been demonstrated that survival and homeostasis of peripheral mature T cells depend on self-recognition. Thus, contrary to previous assumptions, naive T cells apparently require a constant subthreshold signal provided by their engagement with self-major histocompatibility complex (MHC)/peptide ligands to persist in a quiescent state. This self-MHC/peptide recognition in healthy patients provides a proliferation-inducing signal and leads to T-cell expansion but not autoimmunity. However, under the influence of particular background genes, a self-reactive autoimmune disease develops.

Despite key advances in an understanding of immune mechanisms in animal models, our knowledge of the relevant genetic and environmental models remains incomplete. Initial efforts to attribute autoimmunity in humans or mice to simple breakdown in "central" (thymic) tolerance (either with regard to deletions of endogenous superantigen-recognizing T cells or conventional self-peptide-recognizing transgenic mice) have been unsuccessful.

Part of the problem probably involves defects in apoptotic pathways by which activated T cells undergo cell death. However, even in lupus mice that are bred without defects in the proapoptotic FAS pathway, the reasons for underlying excessive activation remain unclear.

Against this background of autoimmunity in mice, many interesting papers were presented at the recent ACR meeting in New Orleans.

Bachmann and coworkers[2] from Oklahoma presented evidence that failure to clear the products of apoptotic cells allows "subdominant" epitopes to become antigenic. Furthermore, frame shift mutations leading to an amino acid substitution in La antigen in one patient led to a loss of a nuclear binding signal and increased antigenicity of the "self-peptide." Although this mutation was documented in a single patient, almost 30% of SLE sera reacted with the neoantigen created in this patient. Naik and coworkers[3] from England emphasized the role of complement C1q to "bridge" these apoptosis-derived subantigenic molecules and increase their ability to be phagocytosed for antigen re-presentation. In the presence of other background lupus genes, this mechanism can perpetuate and expand autoreactive T-cell and B-cell clones.

McClain and colleagues[4] from Oklahoma presented another interesting method for generation of autoimmune B-cell clones. It appears that anti-Ro 60-kd antigen responses in SLE patients begin by targeting an epitope that cross-reacts with the Epstein-Barr nuclear antigen 1. Thus, apoptotic fragments can expand previous immune responses directed against exogenous (ie, Epstein-Barr virus) infections. This is particularly interesting since Epstein-Barr virus is known to have "permanent" residence in the salivary glands and oropharynx of nearly all adults, with periodic exacerbation.

Thus, a variety of candidate antigens derived from apoptotic products can either "break tolerance" or clonally expand by molecular mimicry.

Ramos and coworkers[5] from Minnesota presented the results of a genome-wide search for genetic loci that could predispose to SLE. They found some overlap with previously reported loci (7p21 and 7q11). They also found some linkage with 12q4 (previously associated with multiple sclerosis) and 12q24 (associated with inflammatory bowel disease) and a new association with 15q24. Other studies by Kawasaki and colleagues[6] in Tokyo revealed a tendency to the human BLYS (BAFF/TNFSF13B) locus, including specific nucleotide changes leading to amino acid substitution in the promoter region.

Therapy for SLE
In the area of therapy, azathioprine showed a tendency toward fewer renal relapses after successful cyclophosphamide induction in diffuse proliferative glomerulonephritis, in a study by Mok and coworkers[7] from Hong Kong. The SLE malar rashes were responsive to topical 0.1% tacrolimus, which could possibly avoid the skin thinning noted with potent topical steroids (Jones and colleagues[8] from Florida). Hydroxychloroquine was found to delay the onset of full-blown SLE in patients who present with a positive antinuclear antibody (ANA) (Jonsson and coworkers[9] from Norway) and appeared to be safe in a small number of pregnant women who gave birth while receiving this medication (Costedoat and colleagues[10] of Spain).

Although thalidomide was useful in SLE rashes, neurotoxicity was noted (Cuadrado[11] of the United Kingdom). In a phase 1/2 trial involving 18 patients, anti-CD20 chimeric antibody (rituximab, 100-375 mg/m2) was evaluated throughout 4 weekly doses, with follow-up during 1 year. Although the medication was well tolerated and patients had decreased arthralgias, there was little decrease in anti-DNA titer or improvement in complement levels (Campbell and coworkers[12] from Rochester, New York). In a novel approach to more specific targeting of B-cell therapy, Silverman and colleagues[13] from San Diego reported that protein A will selectively bind to VH3 segments and lead to apoptotic death of this subclass of B cells.

Sjögren's Syndrome
The reports on SS this year largely represented a "consolidation" of observations that had been made in past years based on reevaluation of the data from patient cohorts using the proposed new American-European consensus criteria for SS. These new criteria require either a characteristic biopsy specimen or characteristic autoantibody (ie, SS-A, Ro) in addition to significant objective findings of oral and ocular dryness. The new criteria exclude hepatitis C and other causes of dryness.

Terenzi and coworkers[14] from New York compared patients classified under the European system (EEC) and the new consensus system and found that a main difference was that patients with dryness and fibromyalgia were no longer included in the new consensus criteria. The implementation of new methods to define disease activity and response to therapy is being developed based on scales used in SLE and previous measures called "oral health quality-of-life impact measures."

Using the revised criteria, Witte and coworkers[15] from Germany found an increased frequency of IgA anti-fodrin antibodies (as well as in SLE patients), whereas a separate study of SS patients by Sibilia and colleagues[16] failed to find a significant association with antibodies directed against the fodrin 120-kd fragment that plays a critical role in one murine model of SS (the NFS/sld mouse after thymectomy).

Patients with SS may develop antibodies to a novel centromeric antigen (cen-C), and these patients also recognize SS-A (52 kd) and SS-B (45 kd), according to Pillemer and coworkers[17] of Bethesda. This novel reactivity with a centromeric antigen is distinct from the cen A/cen B, which appears to be an antigenic target in scleroderma patients and helps explain the coexistence of some patients with antibodies to SS-A and yet having an anti-centromeric pattern on their ANA test results. Anti-citrulline antibodies may be present in some SS patients (who are ANA positive and RF negative) and were associated with synovitis previously termed rheumatoid arthritis (RA).

Jonnson and colleagues[18] from Norway reported on the expression of B-cell activating factor (BAFF) in salivary glands, as well as expression of E-cadherin and its integrin ligand aEb7 on the glandular vascular cells and cells infiltrating glandular epithelial cells, respectively. An increased level of Fas and Fas L were again noted, although the level of apoptotic cells was not increased. This activation of early steps of apoptosis appears to lead to glandular dysfunction, as measured by decreased response to muscarinic agonists, even in the absence of apoptotic changes of nuclear fragmentation and cellular blebbing.

Beutler[19] (San Diego) reviewed the important role of cell signaling through TOLL-like receptors to generate apoptotic products. These pathways involve CARD and NOD motif proteins, initially recognized as important elements in the response to lipopolysacharide and now considered as potential agents in the generation of autoantigens that maintain autoimmune T cells (as discussed above). Although distinct from SS, it was also noted that Blau's syndrome (granulomatous uveitis that simulates sarcoidosis) results from mutations in the nod sequences and that familial Mediterranean fever derives from interleukin 1 liberated in unopposed fashion due to mutations in the pyrin gene (Kaster and coworkers,[20] Bethesda), which normally serves as a break on this inflammatory cascade.

Kapsogeorgou and colleagues[21] from Athens reported that glandular cells could release exosomal vesicles that contain potential autoantigens and thus present additional methods to maintain autoimmune T cells similar to those described above for SLE. Lavie and coworkers[22] from France reported that rank and rank ligand, members of the tumor necrosis factor (TNF) superfamily usually associated with bone remodeling, were expressed in the SS salivary gland and could potentially lead to stimulation of T cells and B cells by salivary gland ductal epithelial cells.

Grandis and colleagues[23] from Minnesota reported analysis of complementary DNA made from SS peripheral blood using a microarray of oligonucleotides corresponding to a wide spectrum of inflammatory-related markers. They found at least 2-fold differences in more than 80 genes, including those associated with FAS, protein kinase C, BAFF, and ubiquitin. During the discussion period, the limitations of using blood (a heterogeneous population) to detect small changes in transcription and assay reliability for small changes in transcription were mentioned, but this technology may be useful in monitoring clinical response in particular patients.

Depression as measured by the Center for Epidemiologic Studies--Depression scale was more common in a cohort of SS patients than in age-matched RA patients, according to Reisine and Parke[24] in Connecticut. The dryness symptoms may be further exacerbated by certain antidepressive medications, and the symptoms of dryness (in comparison to objective findings) are further exaggerated by the depression. This creates a vicious cycle for the patient with sleep deprivation and fatigue, as well as a diagnostic and therapeutic difficulty for the rheumatologist.

Sankar and colleagues[25] from Bethesda found that an elevation in serum IgM levels at presentation was associated with a serial decline in salivary gland function as measured by decreased saliva production that occurred in about half of a cohort of 46 patients followed up for 2 years, whereas surprisingly, no association was found with erythrocyte sedimentation rate or IgG levels at presentation. In long-term follow-up studies of SS patients, Quemeneur and coworkers[26] from France found progression of mild interstitial lung disease, which may have been due to aging, as measured by serial pulmonary function tests in 12 patients, for a mean of 10 years.

In a cohort of 110 patients, Ramos-Casals and colleagues[27] from Mexico found a circulating monoclonal protein in 24 patients. Although these patients had extraglandular manifestations such as purpura and pneumonitis, they did not find lymphoproliferative disease (although the length of follow-up of one patient for lymphoproliferative disease was short). In a long-term follow-up of a Greek cohort of patients by Ionnakis and coworkers,[28] purpura and low complement as well as parotid swelling at time of initial evaluation were significant predictors of development of lymphoma at 10-year follow-up.

Different aspects of therapy were presented. Dehydroepiandrosterone was not found to have significant benefit, according to Pillemer and colleagues[29] from Bethesda. Steinfeld and coworkers[30] (Amsterdam) presented favorable results from an open-label trial using infliximab (3 mg/kg) at 0.2 and 6 weeks followed by every 12 weeks in patients with at least one extraglandular manifestation (usually arthritis). These patients were not receiving concurrent methotrexate and had not previously been taking methotrexate.

With the exception of infusion reactions, Steinfeld and colleagues thought that the results were encouraging and noted that the study had now been extended to almost 100 patients with few toxic effects. However, the discussion noted that a safer medication (methotrexate) had not previously failed and that the patients showed wide variation in response (unlike the dramatic response of RA patients to infliximab). Also, the discussion pointed out the potential risks of lymphoma (increased in SS) and potential difficulty in detecting TBC (due to increased frequency of pneumonitis in this population), as well as increased risk of demyelinating disease in this population that could be exacerbated by TNF inhibitors.

Other biologic agents that may undergo trial in SS would be targeted toward B cells, including anti-CD20 (rituximab) for the hemolytic anemia or thrombocytopenia, as well as CTLA-4 Ig or anti-BAFF antibody.

Myositis
Rider and coworkers[31] from Bethesda presented the results of the International Myositis Outcomes Workshop that included 15 adult and 14 pediatric rheumatologists. Muscle strength measured by manual testing was the most important outcome with levels of improvement scored at 15% (mild) to 75% (excellent), since this function correlated with both patient and physician global assessment. Serum levels of muscle enzyme with improvement of 25% to 75% were considered important but less important than objective muscle testing. The same study group noted that extramuscular manifestations (including skin, gastrointestinal, and constitutional) correlated with muscle score and advocated the use of a visual analog scale to measure these variables.

Also of interest, dermatomyositis patients had a different HLA-DRB1 association (DR1*03) than polymyositis (DR1*07) according to Chinoy and colleagues[32] from Manchester.

Fontana and coworkers[33] from Minnesota reported that Coxsackie viral infection of mice leads to a postinfectious sequence of chronic inflammatory myopathy. This led to a lively debate about the risks and benefits of vaccination in patients with autoimmune diseases and those receiving immunosuppressive therapy.

Robin Avery[34] from Cleveland reviewed the current recommendations for vaccines (including attenuated vaccines). The general recommendations were not to use live vaccines in immunocompromised patients, but the data available for patients receiving biologic inhibitors remain incomplete. Although these patients may have suboptimal response to the vaccine, the overall benefit from vaccines against influenza appear to be justified, but varicella and mumps vaccines might be deferred (these are usually administered as combined MMR).

The current influenza vaccines are inactivated and thus differ from the swine flu vaccine of 1976 that was associated with some cases of Guillain-Barré syndrome. The issue of vaccination against smallpox and other bioterrorist agents remains unknown and specific guidelines are being developed. Other live vaccines that have been associated with neuromuscular disorders include tetanus, hepatitis B, and poliovirus; these should be used in higher-risk patients.

Avery[34] of Cleveland reviewed the data on the past proposed complications of the hepatitis B vaccine program in France (called the vaccination panic) that alleged connection of this vaccine and multiple sclerosis, noting that 2 large studies reported last year in the New England Journal of Medicine did not find any connection in large population studies. Chen and colleagues[35] from Pennsylvania reported the occurrence of arthralgias and hearing loss (ie, Cogan's syndrome) 2 weeks after anthrax vaccine. A late-breaking abstract from Brenner and coworkers[36] reviewed 183 complaints of possible anthrax vaccine-related arthritis (occurring within 30 days of vaccination). In 44 cases, they found a possible causal link to the vaccine. The arthralgias appeared self-limited and have not thus far evolved into a recurrent autoimmune disorder. Finally, subclinical myopathy after chloroquine may be more common (up to 5% of treated patients with chloroquine and less than 0.5% with hydroxychloroquine) than expected based on a serial study of 119 patients followed up by Casado and colleagues[37] from Spain.

Muscle biopsy specimens from patients with polymyositis express higher levels of interleukin 1 and TNF in clinically involved muscle than in noninvolved muscle, according to Dorf and coworkers[38] from Sweden. A particular allele in the promoter region of TNF was found by Furuya and colleagues[39] in increased frequency in Japanese myositis patients (38% compared with age-matched controls), suggesting a role for genetic predisposition to myositis.

A similar result was found among American patients, reported by Werth and coworkers[40] from Pennsylvania, who also reported polymorphisms in genes related to mannose-binding proteins that could contribute to increased cytokine levels in involved muscle in polymyositis patients. The muscle biopsy specimens are infiltrated by mature dendritic cells, TH1-type T cells that make interferon gamma and interleukin 17, according to Page and coworkers[41] in France.

In terms of therapy for chronic juvenile dermatomyositis, etanercept was well tolerated but not dramatically effective according to Miller and colleagues[42] of Chicago, whereas infliximab plus methotrexate gave more encouraging results in 3 patients described by Maillard and coworkers[43] from England. Neopterin and quinoloic acid in the urine, as measured by mass spectroscopy by Rider and colleagues[44] in Bethesda, appear to be good surrogate markers for outcome in juvenile idiopathic myositis.

The 3-year outcome results of the National Institute of Arthritis and Musculoskeletal and Skin Disease juvenile dermatomyositis registry (299 patients) were reported by Pachman and coworkers[45] from Chicago: approximately 25% of children continue to have significant weakness and, interestingly, a subset of these children developed psoriasis.