Risk factors for serious infection during treatment with cyclophosphamide and high-dose corticosteroids for systemic lupus erythematosus.

OBJECTIVE: To determine risk factors for serious infection during treatment with cyclophosphamide (CYC) and high-dose corticosteroids in systemic lupus erythematosus (SLE). METHODS: Records of 100 SLE patients who had received CYC were examined for documentation of serious infections that occurred during CYC therapy and the subsequent 3 months. RESULTS: Infection occurred in 45 of 100 patients during CYC therapy. Patients with infection were more likely to have multiple organ disease (49% versus 29%; P = 0.04), a lower nadir in the white blood cell (WBC) count (2,818 versus 3,558 cells/microliter; P = 0.02), and a higher maximum corticosteroid dose (195 versus 73 mg; P < or = 0.01) than patients without infection. Infection occurred with equal prevalence in those who received intravenous (IV) (39%) or oral (40%) CYC, but was more common with use of sequential IV and oral therapy (68%). By multivariate analysis, the strongest association with infection was a WBC nadir < or = 3,000 cells/microliter (odds ratio [OR] 2.8, 95% confidence interval [95% Cl] 1.4-5.5) and use of sequential IV and oral CYC (OR 2.3, 95% Cl 1.2-4.3). Infection occurred in more CYC-treated patients taking concomitant steroids than in those treated with high-dose steroids alone (45% versus 12%; P = 0.001). Fatal and opportunistic infections during CYC therapy were associated with a low WBC nadir and a high maximum corticosteroid dose. CONCLUSION: The risk of serious infection in patients with SLE is influenced by the inclusion of CYC in the treatment regimen. The likelihood of infection in this setting is enhanced by CYC-induced reductions in the total WBC count < 3,000 cells/microliter and by sequential IV and oral therapy. Both of these factors may be indicators of aggressive cytotoxic treatment, underscoring the need for close observation during treatment to minimize the risk of serious infection.

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.

Serologic markers of lupus nephritis in patients: use of a tissue-based ELISA and evidence for immunopathogenic heterogeneity.

In order to assess the ability of various serologic assays to correlate with lupus nephritis, we analysed sera obtained from 60 patients with systemic lupus erythematosus (SLE). Patients were categorized as having active nephritis (group 1), active lupus without nephritis (group 2), inactive lupus with prior nephritis (group 3), or inactive lupus without prior nephritis (group 4). Three parameters were assessed including anti-dsDNA antibodies (Farr assay), immune complexes (C1q binding), and anti-C1q antibodies (salt-stable C1q binding). Additionally, glomerular binding activity (GBA) was measured using a new solid-phase immunoassay that detects immune elements by their ability to bind glomerular tissue. We found that patients with nephritis (group 1) exhibited higher mean values for each assay than patients in each of the other three groups (P = 0.001, 0.009, 0.14, and 0.23 in the GBA, C1q, anti-dsDNA, and anti-C1q assays, respectively). The only assay which distinguished patients with nephritis (group 1) from patients having active disease without nephritis (group 2) was the GBA (mean 0.48 +/- 0.09 versus 0.15 +/- 0.04, P < 0.05). In terms of utility, all tests were specific for diagnosing nephritis among patients with lupus; however, only the GBA was reasonably sensitive. The information provided by the anti-dsDNA and C1q assays were not correlated with one another, nor additive to the GBA. Patients with false negative GBA tended to have received more intensive immunosuppression. The qualitative characteristics of GBA varied among patients with nephritis. These data suggest the pathogenesis of lupus nephritis is complex, and may be mediated by an array of immune elements. Moreover, the data indicate the potential utility for a broad tissue-based approach to detection of pathogenic immune elements over other, specific immunologic markers.

Herpes zoster infections in systemic lupus erythematosus: risk factors and outcome.

OBJECTIVE: To determine factors that influence the frequency and outcome of herpes zoster infection in patients with systemic lupus erythematosus (SLE). METHODS: In this case-central retrospective study, patients with a history of zoster infection were identified from our computerized database of 348 patients with SLE. Medical records were reviewed to establish activity of SLE at the time of zoster, as well as complications of the zoster infection. RESULTS: Fifty-five episodes of zoster occurred among 47 (13.5%) patients, at a rate of 16 episodes/1000 patient-years of followup. Dissemination occurred in 6 episodes (11%), and was more frequent during immunosuppressive therapy [odds ratio (OR) = 4.0]. Bacterial superinfection occurred in 5 (9%), resulting in one death from sepsis, and was increased among patients receiving prednisone > or = 60 mg daily (OR = 4.1). Compared to those without zoster, patients with zoster were significantly more likely to have previously had serious disease manifestations including nephritis, thrombocytopenia or hemolytic anemia, and to have received treatment with cyclophosphamide (all p < or = 0.05). However, 65% of zoster episodes occurred during mild or inactive SLE, when the majority of patients were receiving less than 20 mg prednisone daily and no immunosuppressive therapy. CONCLUSION: Herpes zoster infections occur at increased frequency among patients with SLE compared to the general population, and carry significant morbidity. Patients who have had severe manifestations of lupus are at greatest risk of zoster, though not necessarily at the time of disease flare or immunosuppressive therapy. If disease activity allows, a reduction in prednisone dosage may reduce the risk of bacterial superinfection during zoster episodes.

The spectrum of pericardial tamponade in systemic lupus erythematosus. Report of ten patients.

OBJECTIVE: To describe the range of clinical manifestations and the outcome of pericardial tamponade in patients with systemic lupus erythematosus (SLE). METHODS: Patients with pericarditis and with pericardial tamponade were identified from our computerized database of 395 SLE patients. Medical records were reviewed to establish activity of SLE at the time of tamponade, as well as clinical and laboratory features, treatment, and outcome of the tamponade. RESULTS: Pericarditis occurred in 75 patients (19%), with 11 episodes of tamponade in 10 of them (13%; 2.5% of entire series). Tamponade was the initial manifestation of SLE in 4 patients. Seven episodes occurred during active lupus, with nephritis present in 6. Signs of venous congestion, including ascites and facial or peripheral edema, were the most common manifestation of tamponade. Pericardial fluid was exudative, and pericardial tissue demonstrated a range of findings including fibrinous and fibrotic changes, acute and chronic inflammatory infiltrates, and vascular proliferation. Tamponade was fatal in 1 patient, and 2 patients each had recurrent effusions and pericardial thickening. CONCLUSION: Pericardial tamponade may occur at any point in the course of SLE, and should be considered in patients with unexplained signs of venous congestion. The differential diagnosis includes active SLE, uremia, and infection. Treatment with high-dose steroids and either pericardiocentesis or placement of a pericardial window is indicated, but recurrent effusions or pericardial thickening may develop.

Hyperuricemia and gout among heart transplant recipients receiving cyclosporine.

PURPOSE: To determine the frequency and characteristics of hyperuricemia and gouty arthritis among cyclosporine-treated heart transplant recipients. PATIENTS AND METHODS: One hundred ninety-six surviving adult heart or heart/lung transplant recipients were evaluated. Medical records were reviewed to determine peak serum uric acid levels after transplantation, and to evaluate potential risk factors for hyperuricemia. Patients were surveyed by postal questionnaire for a history of gouty arthritis, with positive responses evaluated by telephone interview and/or examination of the patient. RESULTS: Hyperuricemia occurred in 72% of male and 81% of female patients and was not correlated with cyclosporine level, presence of hypertension, or degree of renal insufficiency. Eleven (6%) patients had gout prior to transplantation; 14 (8%) had onset of definite gout and seven (4%) had probable gout a mean of 17 months after transplantation. Polyarticular arthritis and/or tophi developed in six (43%) of the posttransplant-onset definite gout group within a mean of 31 months. CONCLUSION: Both hyperuricemia and gouty arthritis occur with increased frequency among cyclosporine-treated heart or heart/lung transplant recipients. The clinical course of gout in these patients is often accelerated, with management complicated by the patients' renal insufficiency and interaction with transplant-related medications.

Adrenal insufficiency in two women with anticardiolipin antibodies. Cause and effect?

We describe 2 women with anticardiolipin antibodies and a lupus-like disorder who developed acute adrenal insufficiency. We also review 5 similar cases reported previously. Anticardiolipin antibodies appear to be a risk factor for this vascular complication.

Pregnancy outcomes in women with primary Raynaud's phenomenon.

Pregnancy outcomes were assessed in 67 women who had well-defined primary Raynaud's phenomenon and in 30 controls, each of whom had been pregnant at least once. Twenty-seven patients had onset of Raynaud's phenomenon prior to any pregnancy, and 37 patients had onset of Raynaud's phenomenon after their last pregnancy. The frequency of miscarriage, stillbirth, and small full-term infants was similar in all 3 study groups. Among the 4 Raynaud's phenomenon patients who had second-trimester miscarriages, 2 of 3 who were tested had moderately positive levels of IgG or IgM anticardiolipin antibody. Premature births were significantly more common in pregnancies that occurred after the onset of Raynaud's phenomenon (24%) than in pregnancies that occurred prior to the onset of Raynaud's phenomenon or in pregnancies among control subjects (9% and 1%, respectively). In addition, the mean weight of the full-term babies of women in both Raynaud's phenomenon groups was significantly less than that of babies born to controls. There were no neonatal deaths or other serious adverse outcomes. These findings may represent yet another manifestation of systemic vasospasm in patients with primary Raynaud's phenomenon.

Gout in the heart transplant recipient: physiologic puzzle and therapeutic challenge.

PURPOSE: Hyperuricemia and gouty arthritis have been associated with cyclosporine use in renal transplant recipients. Patients requiring heart or heart-lung transplantation may have additional risk factors for the development of gout, yet it has not previously been described in this population. We share herein our clinical experience with gouty arthritis in six heart transplant recipients. PATIENTS AND METHODS: During a one-year period, six hospitalized male heart transplant patients were seen in consultation for gouty arthritis. Five were subsequently followed for gout as outpatients; the sixth died within six months. Management included trials of nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, allopurinol, and intra-articular steroid injections, as well as attempts to minimize cyclosporine nephrotoxicity. RESULTS: Three patients had gout in remission at time of transplant surgery, and three others developed gout for the first time two to 45 months after transplantation. Following transplant surgery, both pre-existing and new-onset gout appeared to exhibit an accelerated course, with unusually rapid development of chronic polyarticular disease and tophi in four of the five patients followed for more than six months. Peak serum uric acid levels ranged from 11.0 mg/dL to 16.5 mg/dL. NSAIDs produced reversible renal insufficiency in four patients. Gout-related infections occurred in three patients, one of whom died. CONCLUSION: Acute gouty arthritis may occur in the heart transplant recipient despite concomitant use of immunosuppressive drugs. Cyclosporine, with its attendant hypertension and nephrotoxicity, appears to be the major risk factor for hyperuricemia in this setting, leading to the accelerated development of tophi and chronic polyarthritis. Management is complicated by the patients' renal insufficiency and propensity to infection, as well as by interaction with transplant-related medications. Prevention of hyperuricemia by minimizing cyclosporine nephrotoxicity appears to be the best management strategy, with judicious use of allopurinol for those patients in whom this preventive approach fails.

Alpha-1-antitrypsin (PI) and vitamin-D binding globulin (GC) phenotypes in rheumatoid arthritis: absence of an association.

The distribution of alpha-1-antitrypsin (PI) and vitamin D-binding globulin (GC) phenotypes and gene frequencies has been examined in a homogenous group of clinically well-defined patients (N = 81) with rheumatoid arthritis. The distribution pattern of the two markers was then compared with two control groups consisting of 40 individuals with osteoarthritis and 192 randomly selected normal individuals, drawn from the same geographical area as the rheumatoid arthritis patients. No association was observed between alpha-1-antitrypsin subtypes or deficient alleles and any of clinical variables observed in rheumatoid arthritis cases. Although a slightly high frequency of the GC*2 allele and a low frequency of the GC*1S allele were observed in rheumatoid arthritis and osteoarthritis compared to controls, the differences were not statistically significant. However, within the patients two clinical variables were found to be significantly associated with a particular GC phenotype. Periarticular bony erosions and antinuclear antibody were positively and negatively associated with GC 1S-2 phenotype, respectively.

Gangrenous cellulitis associated with gram-negative bacilli in pancytopenic patients: dilemma with respect to effective therapy.

INTRODUCTION: Gangrenous (necrotizing) cellulitis is a progressive bacterial infection of skin and soft tissue; the infection can spread into subcutaneous tissue with involvement of superficial and deep fascia (necrotizing fasciitis). We describe two pancytopenic patients with polymicrobial gram-negative bacteremia and fulminating gangrenous cellulitis. CASE REPORTS: Pseudomonas aeruginosa was isolated from a localized hemorrhagic area of the face in one patient. The chronology of infection in these two patients is documented in a series of dramatic color photographs. Despite appropriate antibiotic therapy, the infections progressed relentlessly and both patients died. COMMENTS: We discuss the dilemma of establishing the correct diagnosis prior to the appearance of the characteristic cutaneous manifestations of hemorrhagic necrosis and gangrene. Once the diagnosis is established, surgical excision is universally recommended. Unfortunately, bleeding diatheses in pancytopenic patients with co-existing coagulation deficiencies pose logistic obstacles in urgent, real-life situations. The timing and conditions for surgery need to be elucidated in these patients. An approach to this infection is proposed. The utility of frozen-section biopsy of the involved tissue and computed tomographic scans of the involved area remains to be evaluated.

Adult rheumatoid arthritis is associated with MC1, a new HLA-D encoded determinant.

We evaluated the association of a new HLA-D encoded determinant, MC1, with adult rheumatoid arthritis (RA). This determinant associates with DR1 and DR4 and can be defined by serological typing. We found MC1 in 83% of 80 patients with RA vs 43% of controls. Although the frequencies of DR1 and DR4 were both significantly increased in patients with RA compared with controls, MC1 had the highest relative risk (6.2) of any HLA-DR antigen tested. MC1 negative and positive populations were not significantly different in any of a variety of clinical and laboratory variables including age, sex, disease duration, age at onset, hours of morning stiffness, functional class, joint count, presence of subcutaneous nodules or bony erosions, frequency of side effects to gold or D-penicillamine, sedimentation rate, and antinuclear antibody.

Musculoskeletal problems in the family practice setting: guidelines for curriculum design.

Rheumatology training is essential for family practice residents, but major inadequacies have been described in current programs. In an effort to guide the design of our own rheumatology curriculum, all patient visits to a family health center over a 15-week period were surveyed. Musculoskeletal problems were reported overall in 23% of the 2285 patient visits and were commoner as patient age increased. Osteoarthritis and regional joint pain were the 2 most frequent problems noted, whereas systemic and inflammatory rheumatic diseases were unusual. Rheumatology curricula for family physicians should stress evaluation, management and prevention of problems in those defined areas.

Malignancy following treatment of rheumatoid arthritis with cyclophosphamide. Long-term case-control follow-up study.

A long-term retrospective case-control study was performed comparing 119 patients with rheumatoid arthritis treated with cyclophosphamide and 119 matched control patients with rheumatoid arthritis not treated with cyclophosphamide to determine the risk of subsequent malignancy. Thirty-seven malignancies were detected in 29 cyclophosphamide-treated patients, while 16 malignancies were found in 16 control patients (p less than 0.05) during a mean follow-up period of more than 11 years. Urinary bladder cancer (six cyclophosphamide-treated patients, no control patients) and skin cancer (eight cyclophosphamide-treated patients, no control patients) were identified as differing statistically between the groups, and hematologic malignancy (five cyclophosphamide-treated patients, one control patient) showed a similar trend. Survival analysis indicated that the rate of development of malignancy in the cyclophosphamide-treated patients was significantly greater than in the control patients at six years following drug initiation, and that this increased rate persisted even at 13 years (p less than 0.01). Of the many risk factors evaluated, mean total cyclophosphamide dose and duration and tobacco use were significantly increased in patients in whom cancer subsequently developed. These long-term complications must be considered seriously when cyclophosphamide or other cytotoxic drugs are initiated for the treatment of rheumatoid arthritis.

Anti-SS-A antibodies and fetal outcome in maternal systemic lupus erythematosus.

In 155 women with systemic lupus erythematosus, there were no significant differences in the rates of fertility or adverse fetal outcome between the 47 (30%) with serum anti-SS-A antibody and the 108 without anti-SS-A, except in the frequency of congenital heart block. This complication occurred in 6 of 96 pregnancies in women with anti-SS-A and was associated with high-titer maternal antibody. The overall risk of a woman with lupus having an infant with congenital heart block was estimated to be 1:60, but the risk was considerably higher (1:20) if anti-SS-A antibody was present.

Prospective evaluation of thyroid function in patients with systemic sclerosis (scleroderma).

A consecutive series of 77 ambulatory, clinically euthyroid patients with systemic sclerosis was evaluated for clinical, chemical and serologic evidence of thyroid disease. Measurements of baseline serum thyroid function tests and the thyroid stimulating hormone response to thyrotropin releasing hormone (TRH) were made. We classified 18 (23%) patients as abnormal, including 8 (10%) who were chemically hypothyroid and 10 (13%) with normal baseline studies but an exaggerated response to TRH injection. The remaining 59 (77%) patients were euthyroid by all measurements. Antithyroid antibodies were present in only 4 of 8 (50%) of the hypothyroid group. There were no differences between the 3 patient groups with regard to the extent of scleroderma, the presence of internal organ involvement, or the frequency of common signs or symptoms of hypothyroidism. Abnormal thyroid function in systemic sclerosis is frequent, often unsuspected clinically, and may occur without markers of autoimmune thyroid disease.

Massive breast enlargement in a patient receiving D-penicillamine for systemic sclerosis.

Breast enlargement is an unusual complication of D-penicillamine therapy for rheumatoid arthritis. We observed breast enlargement and hyperprolactinemia in a woman receiving D-penicillamine for systemic sclerosis. Treatment with danazol was associated with a reduction in both the breast size and the prolactin level.