The devil's in the dosing: severe drug-induced liver injury in a hydroxychloroquine-naive patient with subacute cutaneous lupus erythematosus and porphyria cutanea tarda.

A 29-year-old woman with a 1.5 year history of photosensitive skin lesions on her hands presented with a malar rash, bullous lesions on her hands, and was diagnosed with subacute lupus erythematosus after serologies revealed a positive antinuclear antibody test (1:2560), and antibodies to Ro/SSA and dsDNA. Hydroxychloroquine (400 mg/day) was prescribed and the patient developed severe drug-induced liver injury. Biopsy of her bullous skin lesions was consistent with porphyria cutanea tarda, as were her serological and urinary exams. She was successfully treated with therapeutic phlebotomy. This case identifies porphyria cutanea tarda as an important differential diagnosis for the rheumatologist to consider when evaluating patients with bullous skin lesions. Hydroxychloroquine in lower doses is an effective treatment for porphyria cutanea tarda; at doses used to treat systemic lupus erythematosus and subacute cutaneous lupus, there is a potentially life-threatening complication of hepatotoxicity.

The ratio of erythrocyte sedimentation rate to C-reactive protein is useful in distinguishing infection from flare in systemic lupus erythematosus patients presenting with fever.

Background Both C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) can be elevated in systemic lupus erythematosus (SLE) flare and infection, and are therefore of limited utility for distinguishing between the two conditions in febrile SLE patients. Methods A medical records review of hospitalizations (1997-2006) of SLE patients in the Michigan Lupus Cohort was performed. Eligible hospitalizations were those in which patients presented with a temperature of >100.3°F or with subjective fevers as a presenting complaint at admission. Detailed demographic, clinical, and laboratory data were collected. Multivariable logistic regression was used to examine the associations between ESR and CRP and the outcome of flare vs infection, adjusted for confounders. Results Among 557 SLE patients screened, there were 53 eligible hospitalizations (28 flares and 25 infections). Each unit increase in the ratio of ESR:CRP was associated with a 17% increase in the odds of fever being attributable to SLE flare compared to infection (OR 1.17, 95% CI 1.04, 1.31; p = 0.009), when adjusted for white blood cell count, SLE duration, sex, race, and age. ESR and CRP were not individually associated with flare vs infection when modeled with their ratio. Conclusions The ratio of ESR:CRP may provide diagnostic value beyond individual ESR and CRP levels in distinguishing flare vs infection in SLE patients presenting with fever.

Immunoglobulin (Ig)M antibodies to proteinase 3 in granulomatosis with polyangiitis and microscopic polyangiitis.

Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)-ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3-ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3-ANCA was transient, but could recur. In the second cohort, IgM PR3-ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3-ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3-ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.

Adjunctive GnRH-a treatment attenuates depletion of ovarian reserve associated with cyclophosphamide therapy in premenopausal SLE patients.

BACKGROUND: We measured antimullerian hormone (AMH), a marker of ovarian reserve, in women with lupus treated with cyclophosphamide (CYC) (group I), CYC plus gonadotropin-releasing hormone agonist (GnRH-a) (group II) or neither (group III). We hypothesized that AMH would be diminished in women exposed to CYC versus women receiving adjunctive GnRH-a treatment or no CYC exposure. METHODS: Forty-eight premenopausal lupus patients were retrospectively divided into three treatment groups: CYC alone (group I, n = 11), CYC + GnRH-a (group II, n = 10) and neither (group III, n = 27). Serum AMH levels between groups were compared using a nonparametric test (Wilcoxon rank-sum). Multiple linear regression adjusting for age was performed. RESULTS: AMH (ng/mL) levels at the last collection were significantly lower in group I versus group III (mean ± SD: 0.18 ± 0.20 group I vs 1.33 ± 1.59 group III; p = 0.015), and versus group II (mean ± SD: 0.86 ± 1.06; p = 0.018). When centered on age 30 years, average AMH levels for group I, group II and group III were 0.20, 0.44 and 1.00, respectively. When adjusted for age, AMH between all groups was significantly different (p<0.0001). CONCLUSION: Posttreatment AMH levels were significantly higher among patients receiving CYC + GnRH-a compared to CYC alone, suggesting that GnRH-a coadministration mitigates CYC-induced ovarian injury.

Effects of prasterone (dehydroepiandrosterone) on markers of cardiovascular risk and bone turnover in premenopausal women with systemic lupus erythematosus: a pilot study.

DHEA (dehydroepiandrosterone) is a weak androgen with proposed efficacy in the treatment of mild to moderate lupus, and possible beneficial effects on cardiovascular risk and bone mineral density. We hypothesized that treatment with 200 mg a day of Prasterone (DHEA) would improve pre-clinical measures of atherosclerosis: flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD), and circulating apoptotic endothelial cells (CD 146(AnnV +)), as well markers of bone metabolism. Thirteen premenopausal female patients with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)

Glycosylation of proteinase 3 (PR3) is not required for its reactivity with antineutrophil cytoplasmic antibodies (ANCA) in Wegener's granulomatosis.

OBJECTIVE: The glycosylation status of autoantigens appears to be crucial for the pathogenesis of some autoimmune diseases, since carbohydrates play a crucial role in the distinction of self from non-self. Proteinase 3 (PR3), the main target antigen for anti-neutrophil cytoplasmic antibodies (ANCA) in patients with Wegener's granulomatosis (WG), contains two Asn-linked glycosylation sites. The present study explores the influence of the glycosylation status of PR3 on the PR3 recognition by ANCA in a well characterized population of patients with WG. METHODS: Forty-four patients with WG (459 serum samples) who participated in a multicenter randomized trial, were tested by capture ELISA for ANCA against PR3 and deglycosylated recombinant variants of PR3. RESULTS: The patients were followed for a median of 27 months, and the median number of serum samples per patient was 10. At baseline, the correlation between the levels of ANCA against PR3 and against all the deglycosylated recombinant variants of PR3 were greater than 0.94 (?<0.001 for all the comparisons). Longitudinal analyses comparing the levels of ANCA against PR3 versus all the deglycosylated recombinant variants of PR3, using linear mixed models, showed no significant statistical differences (rho >or=0.90 in all cases). CONCLUSION: The glycosylation status of PR3 has no impact on its recognition by ANCA in WG.

Delayed lupus nephritis.

OBJECTIVE: To describe and analyse the clinical and immunological characteristics of a large series of patients with delayed lupus nephritis (LN). METHODS: A cross-sectional study was carried out. Patients with systemic lupus erythematosus (SLE) who developed renal involvement >or=5 years after the first manifestation(s) of the disease (delayed LN, n = 48) were compared with patients with SLE in whom LN developed within 5 years or less after SLE appeared (early-onset LN, n = 187). A control group, the no LN (NLN) group, comprised patients with longstanding SLE (duration of disease >10 years) who had never shown signs of renal involvement (n = 164). RESULTS: The group with delayed LN was positively associated with Sjögren's syndrome, lung involvement and antiphospholipid syndrome as compared with early LN. However, its renal clinical expression and histopathological patterns were similar to those of early-onset LN. The frequency of anti-dsDNA, anti-Sm and anti-RNP antibodies was higher in patients with LN than in the NLN group, as was the frequency of low complement levels. Jaccoud's arthropathy was a protective factor for nephritis. CONCLUSIONS: Delayed LN is not uncommon in patients with SLE. The identified risk factors might aid in its diagnosis and enhance the ability to identify patients at risk for this complication of SLE.

Autoimmunity to collagen in adjuvant arthritis of rats.

Arthritis can be induced in rats by intradermal injection of oil containing bacterial derivatives (adjuvant-induced arthritis) or cartilage collagen (type II collagen-induced arthritis). It was of interest, therefore, to determine whether collagen functions as an autoantigen in rats with adjuvant arthritis. Blood mononuclear cells from the majority of rats with adjuvant arthritis exhibited enhanced thymidine incorporation to homologous types I and II collagens, as well as to purified protein derivative of tuberculin. In contrast, cells from rats remaining nonarthritic after injection of adjuvant did not respond to collagen, although they did react to tuberculin. Similar results were obtained with a radiometric ear assay used to quantify intradermal delayed-type hypersensitivity in vivo. Using passive hemagglutination, autoantibodies to these collagens and their denatured alpha-chains were frequently detected in the sera of rats late in the course of adjuvant arthritis. Rats with inflammation of a hindlimb induced by turpentine did not acquire sensitivity to collagen. These data indicate that autoimmunity to collagen is a common feature of adjuvant- and collagen-induced arthritis, both of which are considered to be mediated by immunologic mechanisms.

Isolated small-vessel angiitis of the central nervous system.

Isolated cerebral angiitis was confirmed by brain parenchyma biopsy in a 31-year-old man with a rapidly progressive encephalopathy and normal cerebral angiography and magnetic resonance imaging. Presenting features of aphasia, hemiparesis, and lethargy resembled herpes simplex encephalitis. Severe neurologic deficits rapidly resolved with steroids plus cyclophosphamide, and he remains in remission after two years. This case illustrates potentially misleading early manifestations of isolated cerebral angiitis, diagnostic limitations of angiography, the value of biopsy that includes both brain parenchyma and leptomeninges, and the potential efficacy of steroid and cyclophosphamide therapy in small-vessel disease. Clinical features and response to treatment vary widely in reported cases, suggesting that isolated cerebral angiitis may have diverse etiologies.

Atrioventricular conduction in children of women with systemic lupus erythematosus.

The neonatal lupus syndrome consists of transient cutaneous lupus lesions or permanent congenital complete heart block (or hepatic fibrosis), or both, in infants born to mothers with systemic lupus erythematosus (SLE). The frequency of conduction abnormalities was examined in 86 offspring of 53 women affected by SLE. Electrocardiograms from the offspring demonstrated normal sinus rhythm in 84 of 86 offspring. The PR interval was normal for age (< 95th percentile) in 82 offspring and normal for heart rate in 81. Three children had a PR interval > 95th percentile (i.e., first-degree heart block) for both age and heart rate. The PR interval of the other 6 subjects with first-degree heart block for age or heart rate (> or = 95th percentile) was < or = 0.18 second. In contrast, using a rank assignment of PR intervals in relation to heart rate and age derived from published standards, grouped data indicated that heart rate adjusted for age was greater and PR interval adjusted for heart rate longer in offspring of mothers who had the onset of SLE before or during pregnancy than in the normal population; this observation did not hold for offspring whose mothers developed SLE after the pregnancy. These findings indicate that offspring of mothers with SLE, even in the absence of an abnormal electrocardiogram, may have experienced a maternal internal environment that produces subclinical changes in atrioventricular conduction. However, newborns with a normal pulse rate are unlikely to have significant abnormalities in atrioventricular conduction and do not need screening electrocardiograms at birth.

The role of methotrexate in the management of steroid-dependent asthma.

Severe asthma often requires high-dose corticosteroid therapy. However, steroid therapy is fraught with many side effects. There are conflicting reports in the literature regarding the role of methotrexate in reducing the steroid requirements of these patients. This study examined the role of low-dose methotrexate in the management of steroid-dependent asthma. Eleven subjects with stable steroid-dependent asthma were enrolled in a placebo-controlled double-blind crossover trial. Patients received methotrexate, 15 mg/wk, or placebo each for two 12-week periods. There was significant improvement of pulmonary function and reduction of prednisone requirement in both placebo and methotrexate treatment periods. However, methotrexate was not superior to placebo. Only 3 of 11 patients responded to methotrexate. Although low-dose methotrexate therapy may have a role in a small select group of steroid-dependent asthmatics, it provided no additional benefit overall.

Neuropsychiatric lupus.

Neuropsychiatric abnormalities in patients with systemic lupus have been recognized for more than a century. Although the prognosis of lupus has improved, involvement of the nervous system continues to be a major feature, with some abnormality recognized in 50 to 66 per cent of lupus patients. Diagnosis and therapy of neurologic disease remain the most difficult clinical challenges in the management of SLE.

Intravenous cyclophosphamide therapy of severe SLE.

Intravenous cyclophosphamide therapy of severe systemic lupus is associated with reduction in the numbers of circulating T and B lymphocytes, suppression of T11 (CD2) receptor-mediated responses, and suppression of autoantibody production. In clinical trials, intravenous cyclophosphamide plus moderate-to low-dose daily oral prednisone appears to reduce the rate of progression of irreversible renal injury in patients who have active nephritis and definite but limited chronic changes in biopsy specimens. It may also be effective in other forms of severe lupus, although controlled trials are lacking. It may be the treatment of choice in severe lupus characterized by ongoing antibody or immune-complex mediated tissue injury.

Lupus nephritis. Classification, prognosis, immunopathogenesis, and treatment.

There is great variation in the characteristics of renal histology, in its clinical expression and clinical course, and, most likely, in the pathogenic mechanisms of glomerular damage. As the ability to more precisely characterize these lesions improves and as we better understand the multiple pathogenic mechanisms and modulating factors at play in the disease, treatment advances and improved renal survival should follow.

Immunosuppressive drug therapy of systemic lupus erythematosus.

This article reviews the biologic effects of cyclophosphamide and azathioprine relevant to the treatment of systemic lupus erythematosus (SLE). Other agents used less commonly for SLE, such as methotrexate, chlorambucil, and cyclosporin-A, receive more limited attention. Clinical studies of efficacy and toxicity of these agents in their treatment of SLE are then described in detail.

Cyclosporine in the treatment of psoriatic arthritis.

The short-term efficacy of cyclosporine in the treatment of six patients with moderately severe to severe psoriatic arthritis was evaluated in an open study. Patients received oral cyclosporine (6 mg/kg/d) for eight weeks. In all patients, significant improvement of psoriasis was noted within two to four weeks. At the end of therapy, rheumatologic assessment revealed the following trends in disease activity: a decrease in the number of tender joints, joint tenderness index, duration of morning stiffness, and an increase in grip strength. There was a decrease in the number of swollen joints, joint swelling index, and the time taken to walk 50 ft. Overall disease activity significantly improved as assessed independently by the patient and physician. For psoriasis and psoriatic arthritis, disease activity worsened toward baseline within four weeks of discontinuation of therapy. Short-term, low-dose cyclosporine therapy may be effective in treating psoriasis and psoriatic arthritis.

Drug-induced pneumonitis: the role of methotrexate.

Methotrexate (MTX) is a folate antagonist used in several chronic inflammatory and neoplastic conditions. Pulmonary toxicity occurs in 0.5% to 14% of patients receiving low-dose MTX. Manifestations of pulmonary toxicity are protean and include parenchymal inflammation, pneumonia, airway hyperreactivity, air trapping and possibly neoplasm. We performed an exhaustive review of the English literature and identified 189 cases of methotrexate-induced pneumonitis (MIP). Rheumatoid arthritis (RA) was the most frequent underlying disease. In most patients, symptoms present subacutely with progression over several weeks. Most patients present with dyspnea, dry cough, fever, and bibasilar crackles. Peripheral eosinophilia has been cited in one third of cases. The chest radiograph may be normal, but more commonly reveals bilateral interstitial or mixed, interstitial and alveolar infiltrates with a predilection for the bases. Chest computed tomography (CT) scans demonstrate ground-glass opacities, interstitial infiltrates, septal lines or widespread consolidation. Pulmonary function studies reveal a restrictive ventilatory defect and/or impaired gas exchange. Bronchoalveolar lavage (BAL) may be helpful in ruling out an infectious etiology and in supporting the diagnosis of MIP. Cellular interstitial infiltrates, granulomas, fibrosis, atypical epithelial cells, and diffuse alveolar damage (DAD) are the main histologic features. Once MIP is suspected, the MTX should be withdrawn. Corticosteroids may accelerate resolution and are recommended in severe or fulminant cases. The prognosis of MIP is usually favorable, but occasionally the outcome may be fatal.

MRI in osteoarthritis of the hip: gradations of severity.

In a prospective study, 10 patients with well-documented osteoarthritis (O.A.) of the hips were imaged using spin-echo pulse sequences (TR = 0.5 to 1.5 s and TE = 28 to 60 ms). After analyzing the changes observed, an MR grading system for assessing severity of O.A. in the hips was developed. Using this grading system and an established grading system for osteoarthritis using roentgenograms (both systems use grades 0-4), two radiologists independently graded the MR studies and plain films separately, twice. The roentgenogram grading system was more accurate in predicting symptoms in the more severe cases, whereas the MR grading system was slightly more useful in the less severe cases. Our results show that MR can demonstrate a spectrum of changes of O.A. in the hips. Its ability to directly image articular cartilage makes it a powerful research and clinical tool.

Evaluation of knee pain.

Most knee problems are seen first by the patient's primary physician who is thus in a unique position to intervene effectively. This article will emphasize the initial evaluation of patients with nontraumatic disorders of the knee, in which early recognition and therapeutic intervention is most likely to be beneficial.

A case report: the use of ketamine and midazolam intravenous sedation for a child undergoing radiotherapy.

The combination of ketamine hydrochloride and midazolam was used to successfully provide intravenous sedation for a child requiring daily radiation treatments. During the radiation therapy treatments, the anesthesia provider was not in direct contact with the patient. Traditional monitoring was complemented by the addition of closed-circuit television monitoring. The drug combination provided consistent cardiac and respiratory stability, as well as patient immobility, for each radiation treatment.