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| Stuart Levine, M.D.
Treatment Clinical Manifestations | ||
| Treatment | ||
Abstract 1828: Infliximab in the Treatment of Polymyalgia Rheumatica: A Double Blind, Randomized, Placebo Controlled Study Objective: The majority of patients with polymyalgia rheumatica (PMR) can be successfully treated with corticosteroids. However, prolonged treatment is often necessary, increasing the possibility of steroid-related side effects in this elderly patient population. Previous trials with methotrexate as a potential steroid-sparing agent in this condition have been disappointing. As a result, this study addressed whether treatment with the anti-TNF agent Infliximab could be used to prevent relapses and safely decrease corticosteroid dosage and duration in newly diagnosed PMR patients. Methods: A multicenter, double-blind, placebo-controlled RCT was undertaken in Italy. 40 patients with newly diagnosed PMR were enrolled. All patients received 5 infusions of Infliximab at 3 mg/kg or placebo, along with a steroid taper starting at 15 mg and tapered to 0 mg by 16 weeks. The primary study endpoint was the proportion of relapse-free patients through week 22, with the secondary endpoints being the duration of steroid Rx, and the proportion of patients able to completely taper their steroids. Results: At the interim analysis point (week 22), no differences were seen between the groups in the proportion of relapse-free patients (48% Infliximab vs. 58% placebo, p=0.49), duration of steroid Rx (18.2 vs. 18.3 weeks), or percentage of patients able to taper their steroids (45% vs. 62%, p=0.372). Editorial Comment: This study failed to show any benefit of Infliximab use in the treatment of newly diagnosed PMR. The placebo group actually appeared to do slightly better than the Rx group, although the results were not statistically significant. Further, the dose of Infliximab (3mg/kg) chosen was quite low; the possibility that higher doses would lead to different outcomes is possible. The more concerning finding of the trial is the high relapse rate in both groups; this was likely due to the low initial dose of prednisone used, and the overly rapid tapering schedule. We advocate much longer steroid tapers (over 6-12 months, and sometimes longer), and often start at 20mg or sometimes higher for a short period of time if the severity of the symptoms warrant it. Abstract 663: Phase II Study of the Safety and Efficacy of Infliximab in Giant Cell Arteritis (GCA): 22 Week Interim Analysis Objective As with polymyalgia rheumatica (PMR), most patients with giant cell arteritis (GCA) can be successfully treated with corticosteroids. However, prolonged treatment is often necessary, increasing the possibility of steroid-related side effects in this elderly patient population. Again, as with PMR, previous trials with methotrexate as a potential steroid-sparing agent in this condition have been disappointing. As a result, this study addressed the safety and efficacy of the anti-TNF agent Infliximab in the Rx of new-onset GCA. Methods: A multicenter, double-blind, placebo-controlled RCT Phase II study was undertaken. 44 patients with newly diagnosed GCA were enrolled at 22 centers in 5 countries. All patients received 8 infusions of Infliximab at 5 mg/kg or placebo over a 54 week period, along with a steroid taper starting at 40-60 mg/day and tapered on a fixed schedule. The primary study endpoint was the proportion of relapse-free patients through week 22 and safety, with the secondary endpoints being the time to first relapse, cumulative steroid dose, and the proportion of relapse-free patients at 54 weeks. Results: There were more patients with visual changes and fever in the placebo group, but other baseline characteristics were similar. At the interim analysis point (week 22), no differences were seen between the groups in the proportion of relapse-free patients (43% Infliximab vs. 50% placebo, p=0.65), cumulative steroid dose, or days to first relapse. There were relatively few severe adverse events in the trial (1 case of heart failure, several URIs in the Infliximab group). Editorial Comment: As in the PMR trial, this study failed to show any benefit of Infliximab use in the treatment of newly diagnosed GCA. This is the latest trial to reinforce the concept that standard DMARDs do not appear to be efficacious in the treatment of GCA or PMR. This trial used a higher Infliximab dose than the PMR trial, and yet still failed to show improved efficacy over corticosteroids. At this stage, the standard of care for GCA Rx remains prolonged corticosteroid Rx, starting at high doses (we start at 60mg/day), and tapered over a 12 month period. Abstract 1752: Intravenous Immunoglobulins (IVIG) for Relapses of ANCA-Associated Systemic Vasculitides: Final Analysis of a Prospective, Open and Multicenter Trial Objective: To assess the safety and efficacy of monthly IVIG therapy for the treatment of relapsing ANCA-associated vasculitis (AAV). Methods: 20 patients with relapsing AAV who had previously received at least 1 year of steroid Rx and/or other immunosuppression were treated with 6 monthly infusions of IVIG (0.5 g/kg/day x 4 days). Other immunosuppression could be maintained, but not added. Patients were assessed at 9 months for the number of compete and partial remissions, and severity of disease activity at relapse was assessed using the Birmingham Vasculitis Activity Score (BVAS). Results: All 20 patients completed 9 months of follow-up. At the time of first infusion, 19/20 were receiving baseline immunosuppression, and 19/20 were ANCA+. At the 9 month time point, 6 patients had relapsed, and 14 had either a complete or partial remission (12 CR, 2 PR) as defined by the investigators. 65% of the patients with WG achieved CR. Editorial Comment: The French Vasculitis study group has long advocated the use of plasmapharesis for the Rx of vasculitis syndromes (PAN, Churg Strauss, Wegeners, MPA). This study is an extension of their advocacy for non-cytotoxic treatments for the ANCA-associated vasculitides. Given the recent interest in anti B-cell therapies for this group of diseases, it is reasonable to try a modality that is known to increase the clearance of immune complexes from the circulation via inhibitory Fc receptor upregulation. A 6 month trial of monthly IVIG Rx was able to induce complete remissions in 60% of these patients, without increasing or changing background immunosuppression. Although cost and accessibility of IVIG remain important considerations limiting its widespread use in the US, these data support their use in selected ANCA-associated vasculitis patients with relatively preserved renal function, flaring disease and poor tolerance of traditional cytotoxic medications. Abstract 527: Polymyalgia Rheumatica Resistant to Prednisone but Responsive to Methylprednisolone - Mechanisms of Prednisone Resistance Objective: Exquisite steroid responsiveness is one of the hallmarks of polymyalgia rheumatica (PMR). However, there are occasional patients with classic symptoms who do not adequately respond to prednisone. There have been anecdotes in the RA literature describing the efficacy of methylprednisolone (MP) in patients unresponsive to prednisone. This case series describes 4 PMR patients who exhibited a similar response to MP after failing prednisone Rx. The mechanisms of this unusual observation are explored as well. Methods: A case control study of 4 patients with prednisone unresponsive/MP responsive and 4 patients with classic prednisone responsive PMR was performed. All patients were administered 20 mg of prednisone at time 0, and serum was obtained at 2 and 3 hours. Prednisone, prednisolone, IFN-gamma, and IL-6 were measured at each timepoint, and prednisone:prednisolone was measured to assess hydroxylation function in all patients. Results: There were no differences in cytokine production or in hydroxylation ability between the groups, indicating that a defect in prednisone conversion to its active metabolite prednisolone is likely not the mechanism that explains the response variability between the patients to the 2 drugs. The placebo effect is also unlikely, given changes in objective measures such as the ESR and CRP in the MP treated patients. Editorial Comment: Though this small study does not explain the mechanism behind the observation of MP efficacy in pednisone resistant PMR patients, the clinical observation that there is response variability in some patients to different preparations is fascinating. This small study provides a rationale for switching to MP in patients with classic PMR (without GCA signs or symptoms) who do not adequately respond to a prednisone trial. | ||
| Clinical Manifestations | ||
Abstract 429: Vasculitis in Patients with Systemic Lupus Erythematosus: Classification and Impact on the Clinical and Immunological Expression of SLE Objective: Patients with SLE are known to develop systemic vasculitis syndromes which can often be severe and life threatening. However, the prevalence of vasculitis subtypes encountered in SLE, and the risk factors for their development, remain unknown. Methods: A case-control study was performed comparing 670 consecutive SLE patients evaluated at a University clinic and age-matched SLE controls without vasculitis. Vasculitis cases were defined according to the 1992 Chapel Hill Consensus Conference criteria, and angiographic or tissue diagnoses were made in all cases. Results: Strikingly, vasculitis was diagnosed in 11% of SLE patients, and 42% of these fulfilled Chapel Hill criteria for a primary vasculitis syndrome. The remainder was classified as having an SLE-related vasculitis. The most common subtype was small vessel vasculitis (86% of cases). Interestingly, vasculitis was associated with increased SLE disease activity (renal disease, leukopenia, low complements, livedo, presence of antiphospholipid antibodies). Editorial Comment: It has been known for a long time that SLE patients can develop vasculitis syndromes that were largely assumed to be related to the underlying SLE. This study shows for the first time that SLE patients can develop primary vasculitis syndromes, and that these are related to general increases in disease activity. This is critical, given that SLE and severe vasculitis flares are now treated quite differently, especially as pertains to the choice of IV vs. oral cytoxan therapy and the duration of treatment. These data suggest that severe, classifiable, vasculitis in SLE patients should be approached and treated like other primary vacsulitis syndromes. Abstract 517: Trends in the Use of Temporal Artery Biopsy for the Diagnosis of Giant Cell Arteritis (GCA): Experience in 2539 Patients at 3 Centers Over 11 Years Objective: The gold standard for diagnosing GCA is the temporal artery biopsy (TA-Bx). However, the optimal biopsy length and the need for bilateral biopsies are hotly debated issues in the vasculitis literature. This large study of over 2500 patients from a major academic medical center and its affiliates seeks to shed light on both of these issues. Methods: All pathology records from patients undergoing TA-Bx over a 10 year period (1994-2004) were examined. The relationships of both biopsy length and yield of contralateral biopsy after a unilateral negative result to overall positivity were evaluated. Results: Of the 2539 patients evaluated, 27% had a positive TA-Bx. Interestingly, both the length of the biopsy and the number of contralateral biopsies declined over the 10 year period (p<0.001), although this was not correlated with a decline in the number of positive biopsies. 50% of all patients underwent bilateral biopsies. Strikingly, after a negative biopsy, the chance of finding disease on the contralateral side was only 7.4%. Editorial Comment: Over the last several years, it has been proposed that both longer biopsy length and obtaining initial contralateral biopsies should increase the yield of biopsy positivity in patients with suspected GCA. This study seems to cast doubt on these findings. However, it is important to remember that this was a post-hoc analysis of all biopsies performed over a 10 year period; in many cases, the pretest probability of GCA was likely quite low. However, the fact that nearly 10% of contralateral biopsies were positive after an initially negative biopsy serves to reinforce the notion that if the index of suspicion for GCA is high (ie. high ESR, age >70, presence of jaw claudication, scalp or TA tenderness), then contralateral biopsies should be performed routinely given the relatively low morbidity of the procedure and the high risk of not making a timely diagnosis. Astract 1741: Life-Threatening Cryoglobulinemic Vasculitis: Prevalence, Clinical Presentation and Outcome in a Series of 560 Patients with Cryoglobulinemia Objective: Cryoglobulinemia is quite common in patients with hepatitis C infection and a variety of autoimmune and lymphoproliferative diseases, but severe clinical manifestations including vasculitis are quite rare. This study seeks to evaluate the prevalence, features, and outcomes in a well-defined cohort of patients with serologic cryoglobulinemia. Methods: 560 consecutive patients with circulating cryoglobulins were evaluated over a 15 year period. The design was a retrosepective cohort analysis. Results: Consistent with previous data from France, symptomatic cryoglobulinemic vasculitis was noted in 48% of patients with circulating cryoglobulins. However, severe manifestations (ie. organ involvement, and skin involvement other than purpura) were present in a minority of patients (16% of those with symptoms, 8% of total). Despite aggressive medical care, the mortality rate of this subgroup of patients was greater than 50%.< Editorial Comment: This study reinforces the fact that though circulating cryoglobulins are a frequent finding in many patients, severe clinical manifestations are rare. However, when they occur, they can be life-threatening. We therefore advocate very close follow-up of all of our patients with this condition, with frequent monitoring of renal and peripheral nerve function, and close monitoring of all skin lesions to avert the development of ulceration. We also aggressively treat HCV infection whenever possible to mitigate against the development of severe manifestations of the disease. Abstract 667: Solid Malignancies among Wegener's Granulomatosis Patients Treated with Etanercept: Potential Interaction with Cyclophosphamide Objective: The long term adverse effects of adding TNF inhibition to standard immunosuppression is unknown. However, during the Wegeners Granulomamatosis Etanercept Trial (WGET), a higher than expected number of solid tumors was noted in the treatment group compared to the group receiving placebo. This study sought to determine potential explanations for this finding. Methods: 180 patients with Wegeners were followed for a median of 27 months. All data were collected prospectively over the course of the WGET trial. Results: 6 solid malignancies were noted in patients receiving etanercept, and none occurred in the control group (p=0.01). This is in contrast to the # of tumors expected based on standardized age and gender specific incidence rates obtained from the SEER database (1.92 solid tumors, p=0.004). All of the tumors occurred in patients who received both etanercept and cyclophosphamide, though there were no differences between the groups in terms of duration, maximal dose, or prior use of cyclophosphamide. Editorial Comment: This data from the first randomized, double blind, placebo controlled clinical trial in Wegeners granulomatosis show that the combined use of etanercept and cyclophosphamide may increase the risk of solid tumor development. This data, when combined with other recent studies from Europe showing high severe infection and mortality rates in patients treated with Infliximab and cyclophosphamide, should give us pause. At this point, it is clear that the risks of this combination outweigh its clinical benefits, and should be discouraged. However, the finding itself should provide impetus to study the roles of TNF and T cells in solid tumor surveillance in patients with Wegeners granulomatosis. | ||
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