• Wegener's Granulomatosis
• Prednisone in Henoch-Schönlein Purpura
• Behcet's Disease
• Benign Angiopathy of the Central Nervous System
• HBV-Related Polyarteritis Nodosa
• Churg-Strauss Syndrome
• Chlamydia Pneumoniae andTemporal Arteritis

Overview of study: For approximately 15 years, speculation about the efficacy of trimethoprim/sulfamethoxazole (TMP/SMZ; Bactrim; Septra) in Wegeners granulomatosis (WG) has waxed and waned. A randomized, double-masked clinical trial published 5 years ago by this group seemed to indicate that TMP/SMZ (1 DS b.i.d.) is effective in the maintenance of disease remissions in patients with WG. However, only disease flares in the upper respiratory tract appeared to be prevented by TMP/SMZ. The medication has never been tested as a remission induction agent in any trial involving more than a handful of patients. In this study, the investigators used only TMP/SMZ as a remission induction agent in patients with mild WG. The patients included had active "loco-regional" and/or "limited" WG at the time of trial entry. The great majority of patients had only upper respiratory tract disease upon entry in to the trial.

Summary of Findings: Twenty-five of the 31 patients (81%) were enrolled at the time of diagnosis. Six other patients (19%) were enrolled during flares of previously diagnosed disease. Twenty-seven patients (87%) responded to TMP/SMZ, 18 (58%) with complete remission and 9 (29%) with partial remission. Two patients failed to respond, and 2 had the treatment discontinued because of adverse events related to TMP/SMZ. The median time to treatment response was 3 months (range:1-15 months).

During a median of 14 months follow-up, 6 of the 18 patients who had achieved complete remission and 5 of the 9 with partial remission experienced disease flares. Thus, 17 of the 31 patients (55%) of the patients maintained either complete or partial remissions during the period of follow-up. Not surprisingly, the percentage of patients with disease relapses increased with time: an intention-to-treat analysis demonstrated control of disease in 70%, 60%, and 36% at one, two, and three years after trial entry, respectively.

Editorial Comment: Although the potential mechanism of action of TMP/SMZ in WG remains unclear, this study adds further to the notion that in carefully-selected patients with mild disease, TMP/SMZ may be a suitable alternative to immunosuppressive agents, provided that patients are followed very carefully for flares of serious disease.

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Abstract #2029 Chemokine Receptor Expression On CD4-Positive CD45RO-Positive Memory T-Cells In Wegeners Granulomatosis.
P Lamprecht, A Erdmann, A Müller, E Csernok, W Gross.
and
Abstract #2031 CD4-Positive CD28-Negative T-Cells Are The Major Source Of TH-1-like Cytokine Production In Wegeners Granulomatosis.
P Lamprecht, A Komocsi, E Csernok, A Müller, U Seitzer, F Moosig, A Schnabel, W Gross.

Overview of study: In recent years, the importance of chemokine receptors in lymphocyte activation and recruitment has been recognized. In studies reported in the first abstract (2029), the investigators examined the types of chemokine receptors present on peripheral blood CD4+ CD45RO+ T-cells (Granulomatous lesions from patients with WG contain abundant quantities of such cells). The chemokine receptors of interest were CCR3, CCR5, and CXCR3. In the second abstract (2031), the investigators studied the souce of Th1 cytokine production in WG, hypothesizing that it is the CD4+ CD28 negative T-cell.

Summary of Findings: For the studies reported in 2029, peripheral blood mononuclear cells (PBMCs) were isolated from patients with localized WG (n = 5), generalized WG (n = 17), and healthy controls (n = 13). The PBMCs were labeled with fluorochrome-conjugated monoclonal antibodies for cell surface antigens of interest. The expression of CCR3, CCR5, and CXCR3 were determined by flow cytometry. The expression of CCR3 and CCR5 was upregulated both in patients with localized as well as generalized WG, compared to healthy controls. CCR5 expression on CD28-negative CD4+ T-cells was higher in localized WG than in patients with generalized WG (66% versus 12%, respectively; P<0.05).

In the study reported in abstract 2031, the fraction of CD28-negative T-cells was significantly expanded compared with healthy controls (14.4% of the overall CD4+ T-cell population, as opposed to 2.1%; P<0.01). Immunohistologic analyses of respiratory tract biopsies indicated that the majority of T-cells within granulomatous lesions were CD4+ but CD28-negative. In addition, the CD4+ CD28-negative T-cells were the major source of tumor necrosis factor-alpha and interferon-gamma in these lesions.

Editorial Comment: These studies highlight the role of chemokine receptors in WG, particularly that of CCR3 and CCR5. In addition, the CD4+ CD28-negative T-cells appear to drive the Th1 cytokine profile associated with this disease.

Abstract #2030 Influence of CCR5, CCR5^32, RANTES, and MIP Chemokines In Wegeners Granulomatosis.
Y Zhou, D Huang, C Farver, G Hoffman.

Overview of study: In this study, investigators examined the allelic and genotypic frequencies of polymorphisms encoding chemokines and chemokine receptors believed to be important in WG. The study population consisted of 118 Caucasian WG patients and 127 ethnically-matched healthy controls. In addition, the expression of CCR5 and its ligands was examined in 4 lung biopsies from patients with WG, using immunohistochemistry. By way of background, it is essential to note that CCR5^32 is a naturally-occurring variant of CCR5. In CCR5^32, a 32 base-pair deletion results in a non-functioning receptor.

Summary of Findings: Genetic analyses revealed similar allelic frequencies and genotypic distributions of CCR5^32 between patients and controls. However, among the patients who were negative for anti-neutrophil cytoplasmic antibodies (n = 19), none had the CCR5^32 allele. This suggests that CCR5 signaling might exert its most important effect in WG patients with the minimal influence of ANCA. Within the lung biopsies, there was abundant expression of CCR5 as well as RANTES and MIP-1aand - b

Editorial Comment: These studies, combined with the results reported by the German groups in abstracts 2029 and 2031, indicate an important role for CCR5 in WG, and imply that a novel therapeutic strategy might be treatments designed to interfere with the ligation of CCR5.

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Abstract #710 A Randomized, Placebo-Controlled Trial Of Prednisone In Henoch-Schönlein Purpura.
A Huber, N Birdi, J King, P McLaine, T Klassen, M Pothos.

Overview of study: The role of prednisone in the treatment of Henoch-Schönlein purpura (HSP) is not clear. The primary outcome measure in this randomized, multi-center trial from Canada was the presence of nephropathy at one year. At entry, patients were randomized to receive either prednisone (2 mg/kg/day for 7 days, followed by a 7 day taper) or a placebo. During the trial, patients were evaluated at 2 weeks, 1 month, and 1 year.

Summary of Findings: Children aged 2-15 years were enrolled within 7 days of disease onset. The mean age at entry was 6.2 years. All patients had palpable purpura at entry. Eight-eight percent had arthritis, 68% abdominal pain, and 25% renal involvement at baseline. At 1 year, 2 of the 21 patients randomized to prednisone had persistent renal involvement, compared with 1 of the 19 patients randomized to placebo (P = NS). Moreover, there was no difference in renal involvement between the two treatment groups at any time between 1 and 12 months (6 in the prednisone group, 7 in the placebo). Finally, the two groups were essentially identical in terms of the duration of abdominal, joint, and skin symptoms. The investigators concluded that the use of prednisone is not indicated in early HSP.

Editorial Comment: Although this study was small, the lack of benefit of prednisone in most children with HSP appears clear. It is not clear how (or if) the results of this study might be extrapolated to adults with HSP, who are more likely than children to have chronic disease and more likely to suffer serious renal impairment.

Abstract #1309 Long-Term Outcome Of Vision In Behçets Disease.
F Davatchi, F Shahram, H Chams, A Nadji, A-R Jamshidi, C Chams, M Akbarian, F Gharibdoost.

Overview of study: Behçets Disease (BD) occurs sporadically in most Western countries, making the study of large numbers of these patients difficult. One of the most feared complications of BD is ocular involvement, particularly posterior retinitis. Without treatment, this complication may lead to permanent blindness. Albeit corticosteroids, cytotoxic agents, and cyclosporine are effective in treating the ocular manifestations of BD at least temporarily, the long-term ocular prognosis of these patients is often depicted as gloomy despite aggressive intervention. This study from a national treatment center for this disorder in Iran, examined the outcomes of 959 patients with ocular BD. For the purpose of this study, the patients were divided into three groups, based on disease duration: Group 1 (648 patients) = those with disease < 5 years; Group 2 (182 patients) = patients with between 5 and 10 years of disease; and Group 3 (68 patients) = patients with > 10 years of disease.

Summary of Findings: The findings of this study are shown in the table below.

Editorial Comment: Data from this study indicate that the long-term visual prognosis of patients with ocular BD may not be as bleak as often believed. A point of major concern, however, is the fact that data on 61 patients are apparently missing (the total of patients in Groups 1, 2, and 3 is only 898). Were these patients lost to follow-up, or did many suffer other severe complications of BD or its treatment (e.g., central nervous system involvement or opportunistic infections) that led to their lack of inclusion? The outcomes of these missing patients could influence substantially the results of this study, and a full accounting of their data needs to be included in any manuscript of this study submitted for publication.

Abstract #1310 Benign Angiopathy Of The Central Nervous System (BACNS): Analysis of 16 Patients with Clinical Course and Long-term Follow-up.
R Hajj-Ali, A Furlan, A Abou-Chebel, L Calabrese.

Overview of study: In the past few years, it has been recognized that the entity of "central nervous system vasculitis" is actually a heterogeneous group of conditions, likely consisting of many different etiologies. In particular, a sub-group of patients referred to as having "benign" angiopathy of the central nervous system (BACNS), probably has a better prognosis than those patients with true vasculitis of the brain or spinal cord, the so-called primary angiitis of the central nervous system (PACNS). The case series reported in this abstract gives the long-term follow-up of 16 patients with BACNS.

Summary of Findings: The patients reported all met the previously-defined case description of BACNS (J Rheumatol 1993; 20:2046). In general, the patients had relatively acute onsets of neurological dysfunction. All had highly abnormal cerebral angiograms, and more than three-fourths of the patients had abnormal magnetic imaging studies of the brain. However, all patients except for 1 had normal lumbar punctures.

The majority of patients were female, with a female ratio of > 4:1. The most common complaint on presentation was headache (88%), but 63% of patients also had neurological symptoms that were focal and 44% had symptoms that were diffuse. All patients were treated with less than 6 months of corticosteroids, and none received cytoxic agents. Many patients were treated with a calcium channel blocker to prevent vasospasm. On follow-up, the patients as a group had three characteristics: 1) rapid resolution of angiographic abnormalities (typically within one month); 2) marked improvement in >90% of patients; and, 3) rarity of disease recurrence (1 patient only). Telephone interviews with patients using the Barthel Index indicated that 71% had no residual disability, and 29% had only mild residual disability.

Editorial Comment: Central nervous system "vasculitis" can be mimicked by many disease entitites. In fact, the frequency of occurrence of the mimickers probably outnumbers the cases of true vasculitis by a significant margin. The natural history of BACNS suggests that most of these cases are probably induced by some agent or stimulus that induces vasospasm. This vascular response typically reverses rapidly, and does not require prolonged treatment with immunosuppression. Patients who meet the profile of a BACNS case should probably be treated with corticosteroids if there are focal neurological deficits, but consideration should be given to repeating cerebral angiography 4-6 weeks after the initiation of treatment. Resolution of the original angiographic findings during this period should lead to tapering of corticosteroids completely with several months, or sooner.

Abstract #1311 Treatment Of HBV-Related Polyarteritis Nodosa (PAN) With Lamivudine And Plasma Exchanges: A Prospective, Multicenter, Pilot Trial in 10 Patients.
L Guillevin, P Cohen, C Larroche, V Queyrel, V Loustaud-Ratti, B Imbert, P Hausfater, J Ramanoelina, F Lacombe, J Roudier, P Bielefeld, P Petitjean, D Smadja.

Overview of study: The association between hepatitis B virus (HBV) infections and PAN was first recognized in 1970. Only now, however, are physicians armed with an effective, novel treatment for patients who develop PAN in the setting of HBV. The availability of lamivudine has dramatically changed the treatment paradigm for patients whose disease is caused by this virus. In this study, 10 patients with HBV-associated PAN, all newly-diagnosed, were treated with a short course of corticosteroids (total 2 weeks), plasma exchange (3X weekly for 3 weeks, 2X weekly for 2 weeks, and then once weekly until the achievement of remission), and lamivudine 100 mg/day until seroconversion to anti-Hbe antibody positivity status was confirmed.

Summary of Findings: All 10 patients presented with symptoms and signs suggesting classic PAN, i.e., vasculitis limited to medium-sized muscular arteries. All patients were negative for anti-neutrophil cytoplasmic antibodies, and renal involvement when present was characterized by renovascular hypertension and renal infarction, rather than by glomerulonephritis. The Five Factor Scores of the patients at presentation were: 5 (1 patient), 3 (1), 2 (2), and 0 (6). During follow-up, 1 patient died of septicemia when treated with corticosteroids for a fever in the mistaken belief that the fever was caused by PAN. Clinical recoveries were obtained in the other 9 patients, with no relapses. Seroconversion to anti-Hbe antibody positivity occurred in 6 of these 9 patients after a mean of 158 +/- 81 days.

Editorial Comment: This treatment regimen for HBV-associated PAN appears to be safe, well-tolerated, and effective. The majority of patients included in this study, however, had mild disease. Full scrutiny of the data in a peer-reviewed publication and use of this regimen in greater numbers of patients are required before the full utility of this regimen can be realized. It is possible that longer courses of corticosteroids would be useful in some patients with disease at the severe end of the spectrum at presentation.

Abstract #1312 Corticosteroids And 6 Vs. 12 Cyclophosphamide Pulses For Churg-Strauss Syndrome With Initial Poor-Prognostic Factors: Preliminary results at 4 years of a French multicenter prospective randomized trial.
P Cohen, L Mouthon, P Godmer, M-H Andra, J-P Aréne, P Casassus, J-F Cordier, L Guillevin, the French Vasculitis Study Group.

Overview of study: Although Churg-Strauss syndrome (CSS) is often believed to respond to corticosteroids alone and not to require cytotoxic agents, this unfortunately is not always the case. In this randomized trial conducted by the French Vasculitis Study Group, patients with CSS who had Five Factor Scores of > 1 at baseline were randomized to receive a regimen of corticosteroids plus either 6 or 12 treatments with intravenous cyclophosphamide (600 mg/m² of body surface area). The purpose of the trial is to determine the optimal length of cytotoxic therapy in patients with this disease. In this abstract, preliminary results of the trial are reported.

Summary of Findings: To date, 39 patients have been enrolled, 18 into the 6-month arm and 21 into the 12-month arm. In the 6-month arm, 83.3% have entered complete remission, compared with 76.2% in the 12-month arm. Four patients (2 in each arm) have died: 2 of cardiac failure, 1 of infection, and 1 of uncontrolled vasculitis.

Editorial Comment: Based on these preliminary results, there does not appear to be any reason to favor the longer course of monthly cyclophosphamide. Full results should be available from this trial within 2 years.

Abstract #2028 Chlamydia Pneumoniae And Temporal Arteritis: No Association by Polymerase Chain Reaction Analyses of Temporal Artery Biopsies.
M Regan, B Wood, Y-H Hsieh, M Theodore, T Quinn, D Hellmann, W Green, C Gaydos, J Stone.

Overview of study: Temporal arteritis (TA) is a vasculitis of medium- to large-sized arteries that affects elderly individuals almost exclusively. Atherosclerosis, another inflammatory disorder of medium- to large-sized arteries with a predilection for older individuals, has been associated in recent years with Chlamydia pneumoniae infections (although the true relationship remains uncertain). Small studies and case reports have also linked TA with C. pneumoniae, detected by polymerase chain reaction (PCR) or immunohistochemistry within the walls of temporal arteries. This large study, which examined the temporal artery biopsies from 90 biopsy-proven cases of TA by PCR and compared the results from those obtained by examining 90 control biopsies, casts major doubt on the role of C. pneumoniae in the etiopathogenesis of TA.

Summary of Findings: All 90 cases met the 1990 American College of Rheumatology criteria for the classification of TA, and all had positive biopsies. The controls were selected from a group of individuals who underwent temporal artery biopsies at the same institution during the same period as the cases, but who had negative biopsies. All of the original biopsies were reviewed to confirm the original readings, and the charts of potential controls were reviewed to ensure that they did not have post-biopsy courses consistent with biopsy-negative TA. Each case was matched to a control on gender, year of biopsy, and age within 10 years.

Two sets of CDC-recommended PCR primers were employed. The 2 primer sets target 2 different C. pneumoniae genes. Using the primer set targeting the ompA gene in a nested PCR assay, 1 case biopsy and 1 control biopsy was positive. In the confirmatory studies that employed primers targeting the 16S rRNA gene in a touchdown enzyme, time-released PCR assay, none of the cases and none of the controls were positive. Spiking experiments eliminated the possibility of PCR inhibitors as a possible explanation for these negative findings, and human DNA was amplifiable in 100% of specimens tested (28/28).

Editorial Comment: The negative results of this carefully-performed study indicate that a role for C. pneumoniae in the propagation of TA is highly unlikely. Because a "hit-and-run" mechanism cannot be excluded, it is still possible that C. pneumoniae contributes to the initiation of disease but is no longer detectable during the period in which clinical disease is apparent.

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