Pre-treatment affinity for LJP 394 influences pharmacodynamic response in lupus patients.

Five prospective clinical studies in lupus patients have shown that LJP 394 can reduce circulating anti-dsDNA antibody levels without causing generalized immunosuppression. The compound is currently being evaluated in a phase III clinical trial for the prevention of renal flares in patients with high-affinity antibodies to LJP 394 and a history of lupus nephritis. The current study analyzed the affinity of patient IgG for LJP 394 prior to and following 4 months of treatment with LJP 394 to determine if pretreatment affinity influenced pharmacodynamic response. Patient serum samples from a multicenter, double-blind, placebo-controlled trial were evaluated prior to and following 4 months of weekly, biweekly or monthly treatment with placebo (n = 9) or weekly treatment with 10 mg LJP 394 (n = 6) or 50 mg LJP 394 (n = 4). After treatment there was a dose-dependent reduction in affinity in the 10 mg/week and 50 mg/week groups (P < 0.05 and P < 0.01, respectively), whereas the placebo group was unchanged. This study demonstrates that weekly treatment with LJP 394 produces a dose-dependent reduction in titer-weighted average affinity. These results suggest it may be possible to use an affinity assay to define prospectively patients that are most likely to exhibit the desired pharmacodynamic response to LJP 394.

Treatment of systemic lupus erythematosus with LJP 394.

OBJECTIVE: LJP 394 is a novel therapy under development for the treatment of systemic lupus erythematosus (SLE). We investigated the optimal LJP 394 dosing regimen required to maximally reduce serum dsDNA antibodies. We also evaluated the safety and tolerability of repeated doses of LJP 394 as well as the effects of therapy on SLE related disease activity and health related quality of life. METHODS: This was a multicenter, partially randomized, placebo controlled, double blind, dose-ranging trial. Study drug or placebo was administered at weekly, biweekly, or monthly intervals for a total of 17, 9, or 5 doses, respectively. Fifty-eight patients were randomly assigned to receive 1, 10, or 50 mg LJP 394 or placebo. After a 2 month pretreatment period, dosing visits continued for 16 weeks, after which there was a 2 month posttreatment period. RESULTS: The greatest reductions in mean dsDNA antibody titers were observed in the group of patients who received 50 mg LJP 394 weekly (38.1% and 37.1 % at Weeks 16 and 24, respectively). A reduction (29.3%) in dsDNA antibody titers was also observed at Week 24 in the group of patients who received 10 mg LJP 394 weekly. The frequencies of adverse events were comparable in the placebo and active treatment groups. CONCLUSION: This clinical trial, in which a large number of patients with SLE were treated with LJP 394, expanded the safety profile of LJP 394 and demonstrated its capacity to reduce dsDNA antibodies.

Familial clustering of rheumatoid arthritis with other autoimmune diseases.

Previous studies have shown that rheumatoid arthritis aggregates within families. However, no formal genetic analysis of rheumatoid arthritis in pedigrees together with other autoimmune diseases has been reported. We hypothesized that there are genetic factors in common in rheumatoid arthritis and other autoimmune diseases. Results of odds-ratio regression and complex segregation analysis in a sample of 43 Caucasian pedigrees ascertained through a rheumatoid arthritis proband or matched control proband, revealed a very strong genetic influence on the occurrence of both rheumatoid arthritis and other autoimmune diseases. In an analysis of rheumatoid arthritis alone, only one inter-class measure, parent-sibling, resulted in positive evidence of aggregation. However, three inter-class measures (parent-sibling, sibling-offspring, and parent-offspring pairs) showed significant evidence of familial aggregation with odds-ratio regression analysis of rheumatoid arthritis together with all other autoimmune diseases. Segregation analysis of rheumatoid arthritis alone revealed that the mixed model, including both polygenic and major gene components, was the most parsimonious. Similarly, segregation analysis of rheumatoid arthritis together with other autoimmune diseases revealed that a mixed model fitted the data significantly better than either major gene or polygenic models. These results were consistent with a previous study which concluded that several genes, including one with a major effect, is responsible for rheumatoid arthritis in families. Our data showed that this conclusion also held when the phenotype was defined as rheumatoid arthritis and/or other autoimmune diseases, suggesting that several major autoimmune diseases result from pleiotropic effects of a single major gene on a polygenic background.

T cell receptor peptide vaccination in rheumatoid arthritis: a placebo-controlled trial using a combination of Vbeta3, Vbeta14, and Vbeta17 peptides.

OBJECTIVE: Restricted T cell receptor (TCR) gene usage has been demonstrated in animal models of autoimmune disease and has resulted in the successful use of TCR peptide therapy in animal studies. This clinical trial was undertaken to determine the safety and efficacy of a combination of Vbeta3, Vbeta14, and Vbeta17 TCR peptides in Freund's incomplete adjuvant (IFA) in patients with rheumatoid arthritis (RA). METHODS: A double-blind, placebo-controlled, multicenter, phase II clinical trial was undertaken using IR501 therapeutic vaccine, which consists of a combination of 3 peptides derived from TCRs (Vbeta3, Vbeta14, and Vbeta17) in IFA. A total of 99 patients with active RA received either 90 microg (n = 31) or 300 microg (n = 35) of IR501 or IFA alone (n = 33) as a control. The study medication and placebo were administered as a single intramuscular injection (1 ml) at weeks 0, 4, 8, and 20. RESULTS: Treatment with IR501 was safe and well tolerated. None of the patients discontinued the trial because of treatment-related adverse events. Efficacy was measured according to the American College of Rheumatology 20% improvement criteria. Using these criteria, patients in both IR501 dosage groups showed improvement in disease activity. In the most conservative analysis used to evaluate efficacy, an intent-to-treat analysis including all patients who enrolled, the 90-microg dosage group showed a statistically significant improvement compared with control patients at the 20-week time point after the third injection. Trends toward improvement were shown in both the 90-microg and the 300-microg dosage groups at week 24 after the fourth injection. CONCLUSION: IR501 therapeutic vaccine therapy was safe and well tolerated, immunogenic, and demonstrated clinical improvement in RA patients. Additional clinical trials are planned to confirm and extend these observations.

The connection between chronic fatigue syndrome and neurally mediated hypotension.

Research from several groups of investigators indicates that some patients with chronic fatigue syndrome have abnormal vasovagal or vasodepressor responses to upright posture. If confirmed, these findings may explain some of the symptoms of chronic fatigue syndrome. There is also speculation that neurally mediated hypotension may be present in fibromyalgia. This article discusses the original research in this area, the results of follow-up studies, and the current approach to treating patients with chronic fatigue syndrome in whom neurally mediated hypotension is suspected.

Does methotrexate increase the risk of infection or malignancy?

Most patients do not exhibit overt signs of immunosuppression. Studies cited in this article support a modest increase in the rate of bacterial respiratory and skin infections. Opportunistic infections occur rarely, however, and may be life threatening. The case for MTX carcinogenicity is less clear. The risk for malignancy other than lymphoproliferative disorders does not seem to be elevated, although multiple sporadic malignancies have been reported in treated patients. MTX is a superb agent for the therapy of a large group of immune-mediated diseases. Although an increased risk for infection and possible malignancy exists, the risk is small compared with the potential clinical benefit.

Mediastinal mass and hilar adenopathy: rare thoracic manifestations of Wegener's granulomatosis.

OBJECTIVE: To assess the frequency and characteristics of hilar and mediastinal involvement in patients with Wegener's granulomatosis (WG). METHODS: A patient with WG presented with the unusual finding of a mediastinal mass, prompting a comprehensive review of 302 patient records from 2 WG registries to obtain evidence of hilar adenopathy or mediastinal masses. Clinic progress notes and findings of chest imaging studies (routine imaging and computed tomography) were reviewed for the presence of hilar lymphadenopathy, mediastinal masses, or mediastinal lymphadenopathy. All radiographs and surgical pathology specimens from these lesions were reviewed. RESULTS: Six examples of mediastinal or hilar involvement (2.0%) were identified among 302 patients with WG. Three of these 6 patients had mediastinal masses. One patient with a mediastinal mass also had mediastinal lymphadenopathy. Two of the patients with mediastinal masses had lung parenchymal lesions. The remaining 3 patients had enlarged hilar lymph nodes in addition to pulmonary parenchymal lesions. All of the patients were treated with corticosteroids and cytotoxic drugs. Followup information was available on all patients. Two patients died. In the remaining 4 patients, the mediastinal mass or hilar lymphadenopathy decreased in size or resolved after 2 months of immunosuppressive therapy. CONCLUSION: In the past, hilar adenopathy and/or mediastinal mass have been considered unlikely features of WG, and their presence has prompted consideration of an alternative diagnosis. Although this caution remains valuable, the present retrospective review of data from 2 large WG registries illustrates that such findings may rarely be a part of the spectrum of WG chest disease. Because these findings are uncommon, they necessitate consideration of a primary or concurrent infection or malignancy in the diagnostic evaluation.

Alveolar hemorrhage in patients with rheumatic disease.

Alveolar hemorrhage is an uncommon event that is associated with several underlying disorders, many of which are immunologically mediated. Careful evaluation of basic laboratory tests, extrapulmonary physical findings, and serology usually leads to the correct diagnosis. Significant overlap, however, exists, and pathologic (especially immunopathologic) evaluation of pulmonary or renal biopsies may be necessary. An accurate diagnosis is essential because treatment is most helpful when directed at the underlying diagnosis. Supportive therapy may be needed until the underlying disease is diagnosed and specific therapy is initiated.

Severe multicentric reticulohistiocytosis: disease stabilization achieved with methotrexate and hydroxychloroquine.

Multicentric reticulohistiocytosis is a rare systemic disease that typically manifests as erosive polyarthritis. The particularly aggressive nature of multicentric reticulohistiocytosis has led many to recommend treatment with high dose corticosteroids, alkylating agents, or both. We describe a 56-year-old woman with erosive polyarthritis successfully treated exclusively for 30 months with hydroxychloroquine and methotrexate. This regimen may have the potential to provide longterm disease control with reduced risk of serious drug related toxicity.

Managing lupus nephritis: algorithms for conservative use of renal biopsy.

SUMMARY: Despite the widespread use of renal biopsy to guide the treatment of lupus nephritis, the disease can usually be diagnosed and managed on the basis of its clinical presentation alone. We propose a conservative approach in which biopsy is used selectively and present three algorithms that allow for a simplified initial approach to managing lupus nephritis. KEY POINTS: Although the grading systems of the World Health Organization and the National Institutes of Health for renal biopsy results are commonly used to guide the treatment of lupus nephritis, there are limits to the utility of these systems. Physicians can distinguish clinically mild lupus nephritis, the nephrotic syndrome, or the nephritic syndrome on the basis of the urine sediment, urine protein excretion, serum albumin and creatinine concentrations, and creatinine clearance, and can initiate treatment on the basis of this information, rather than performing a renal biopsy. Corticosteroids are the cornerstone of therapy for lupus nephritis, but new therapies are emerging. The nephritic syndrome reflects active disease and requires more vigorous treatment. It may be prudent to reserve renal biopsy for situations that arise later in the course of lupus nephritis, such as failure to respond to therapy based on the initial clinical presentation.

Rheumatic manifestations of dysproteinemias and lymphoproliferative disorders.

Rheumatic manifestations may be the presenting features of dysproteinemias and lymphoproliferative disorders. Disease or therapy-related complications may mimic a number of primary rheumatic syndromes. This article emphasizes clinical aspects pertaining to prompt diagnosis and therapy.

Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year followup study.

OBJECTIVE: To examine the effects of cyclophosphamide (CYC) on the development of malignancies and on the long-term survival of patients with rheumatoid arthritis (RA). METHODS: We used a longitudinal cohort design in which 119 patients (76 women and 43 men) with refractory RA who were treated with oral CYC between 1968 and 1973 were compared with 119 control patients with RA (matched for age, sex, disease duration, and functional class) who were evaluated during the same time period but did not receive CYC. RESULTS: There was increased risk of malignancy in the CYC-treated group, with 50 cancers found in 37 patients in the CYC group compared with 26 cancers in 25 of the control patients (P < 0.05). The relative risk of cancer for those treated with CYC was 1.5 (95% confidence interval 0.93-5.5). Nine of the malignancies in the CYC group were bladder cancers and 19 were skin cancers, compared with no bladder cancers and 6 skin cancers in the control group. The total dose of CYC was higher in those who developed cancer, particularly in those with bladder cancer. Three of the bladder cancers occurred 14, 16, and 17 years after CYC had been discontinued. CONCLUSION: The risk of malignancy, particularly bladder cancer, in RA patients treated with oral CYC continues even 17 years after discontinuation of the drug.

CT of dystrophic calcification in subcutaneous soft tissues secondary to chronic insulin injection.

We describe a case of massive dystrophic subcutaneous calcification in the anterior thighs of a long-term insulin-dependent diabetic.

Refractory rheumatoid arthritis. Therapeutic options.

Because rheumatoid arthritis rarely remits, refractory disease is common. Attention should be paid to aggravating comorbid conditions. Pharmacologic options currently available include cyclosporin, high-dose methotrexate, combination second-line agents, and creative use of corticosteroids. The available literature is reviewed in this article and the potential risks and benefits of the various options are discussed.

Treatment of refractory psoriatic arthritis.

Psoriatic arthritis occurs in approximately 5% of patients with psoriasis and can lead to significant morbidity. Treatment options for refractory psoriatic arthritis can be divided into (1) medications used in the treatment of other rheumatic diseases and (2) experimental agents. This article reviews available therapeutic agents for psoriatic arthritis and outlines an approach to treatment. The use of physiotherapy and surgery and the management of arthritis mutilans are also reviewed.

Treatment of refractory cutaneous lupus erythematosus.

Photoprotection, topical steroids, and hydroxychloroquine are the mainstays of therapy of cutaneous LE. In severe and/or refractory disease, antimalarials remain the drugs of choice, and multiple induction and combination strategies can be employed to achieve optimal results with minimal toxicity. Retinoids, dapsone, clofazimine, and thalidomide are effective but more toxic alternatives. Their use dictates frequent and careful monitoring. Retinoids and thalidomide are teratogenic, and thalidomide is not available in the United States. Results with vitamin E are controversial. Gold and IFN-alpha have unacceptably high risk to benefit ratios. Cytotoxic agents are generally restricted to the patients with concomitant organ-threatening systemic disease.

Is malignancy a major concern in rheumatoid arthritis patients?

There are several major issues related to malignancy that are of importance to the practicing clinician caring for patients with rheumatoid arthritis. Although it has been clearly established that rheumatoid arthritis is associated with an increased risk of hematologic malignancies including non-Hodgkin's lymphoma and multiple myeloma, the absolute risk of developing a hematologic malignancy is less than 1%. In rheumatoid arthritis patients with secondary Sjogren's syndrome, Felty's syndrome, or paraproteinemia, the risks for developing hematologic malignancy are likely to be even higher. These risks are balanced by reduced rates of gastrointestinal cancers. There are no conclusive data that link the FDA-approved second line therapeutic agents with the subsequent development of malignancy. However, the renal transplant experience suggests that immunosuppression alone increases the risk of subsequent malignancy. This should be a guiding principle when obtaining informed consent as well as in planning future therapeutic approaches to rheumatoid arthritis. Alkylating agents markedly increase the risk of leukemia and skin, bladder, and hematologic malignancies when used to treat rheumatoid arthritis.

Fever and Cough in Methotrexate-treated Patients: An Approach.

The prevalence of acute methotrexate pneumonitis is up to 5.5%. Its presentation is often difficult to distinguish from opportunistic infections such as Pneumocystis carinii, nocardia, and cryptococcus or from interstitial infiltrates from the underlying rheumatic disease. Its recognition rests on the presence of cough, dyspnea, fever, new pulmonary function test abnormalities, and acute infiltrates on chest radiograph. The diagnosis ultimately rests on histologic confirmation and exclusion of infection. Bronchoalveolar lavage for cultures, and special staining of lavage and transbronchial histopathology specimens, often allows identification of opportunistic pathogens. Transbronchial biopsy may provide sufficient material for the diagnosis of either methotrexate pneumonitis of rheumatoid lung, particularly when correlated with the clinical presentation. Open lung biopsy should be considered if a diagnosis cannot be obtained on bronchoscopy. Despite a mortality of up to 10%, methotrexate pneumonitis usually responds to discontinuation of the drug and trial of corticosteroids.

Methotrexate: the emerging drug of choice for serious rheumatoid arthritis.

The recently recognized high morbidity and unexpected mortality associated with rheumatoid arthritis (RA) has spurred new interest in more aggressive, early treatment of this disease. Methotrexate (MTX) has rapidly become the rheumatologist's drug of choice for serious RA because of its favorable efficacy to toxicity ratio and rapid onset of action compared with other second-line agents. The initial concerns about hepatic fibrosis and cirrhosis in psoriatic patients has subsided somewhat as long-term liver toxicity data are accumulating in patients with RA. Routine liver biopsy with incremental doses of MTX is no longer recommended. Potential for severe lung, hematologic, and infectious complications exists, mandating careful monitoring of RA patients taking MTX.