Factors associated with poor outcomes in patients with lupus nephritis.

The objective of this study was to identify the factors associated with important clinical outcomes in a case-control study of 213 patients with lupus nephritis. Included were 47% Hispanics, 44% African Americans and 9% Caucasians with a mean age of 28 years. Fifty-four (25%) patients reached the primary composite outcome of doubling serum creatinine, end-stage renal disease or death during a mean follow-up of 37 months. Thirty-four percent African Americans, 20% Hispanics and 10% Caucasians reached the primary composite outcome (P < 0.05). Patients reaching the composite outcome had predominantly proliferative lupus nephritis (WHO classes: 30% III, 32% IV, 18% V and 5% II, P < 0.025) with higher activity index score (7 +/- 6 versus 5 +/- 5, P < 0.05), chronicity index (CI) score (4 +/- 3 versus 2 +/- 2 unit, P < 0.025), higher baseline mean arterial pressure (MAP) (111 +/- 21 versus 102 +/- 14 mmHg, P < 0.025) and serum creatinine (1.9 +/- 1.3 versus 1.3 +/- 1.0 mg/dL, P < 0.025), but lower baseline hematocrit (29 +/- 6 versus 31 + 5%, P < 0.025) and complement C3 (54 +/- 26 versus 65 + 33 mg/dL, P < 0.025) compared to controls. More patients reaching the composite outcome had nephrotic range proteinuria compared to controls (74% versus 56%, P < 0.025). By multivariate analysis, CI (hazard ratio [95% CI] 1.18 [1.07-1.30] per point), MAP (HR 1.02 [1.00-1.03] per mmHg), and baseline serum creatinine (HR 1.26 [1.04-1.54] per mg/dL) were independently associated with the composite outcome. We concluded that hypertension and elevated serum creatinine at the time of the kidney biopsy as well as a high CI are associated with an increased the risk for chronic renal failure or death in patients with lupus nephritis.

Maintenance therapies for proliferative lupus nephritis: mycophenolate mofetil, azathioprine and intravenous cyclophosphamide.

For the treatment of proliferative lupus nephritis, long-term cyclophosphamide (CY) regimens are efficacious, however, at the expense of substantial toxicity. In the last decade, sequential regimens of short-term CY induction followed by either mycophenolate mofetil (MMF) or azathioprine (AZA) maintenance have shown to be efficacious and safe reducing the long-term exposure to CY. In a maintenance study including predominantly Hispanics and African-Americans, the patients who received MMF and AZA maintenance had a higher cumulative probability of remaining free of the composite of death or chronic renal failure (CRF) compared to quarterly intravenous CY (IVCY) maintenance (89% in MMF, 80%, in AZA and 45% in IVCY). Likewise, MMF and AZA maintenance were associated with significantly lower incidence of severe infections (2% in each MMF or AZA, and 25% in IVCY), sustained amenorrhea (6% in MMF, 8% in AZA, and 32% in IVCY), and hospitalizations (one hospital-days per patient-year in each MMF or AZA, and 10 in IVCY). In a European induction study including predominantly Caucasians, patients who received any of two sequential regimens, low dose versus high dose IVCY induction both followed by AZA maintenance, had a high cumulative probability of remaining free of treatment failure (84% in low dose IVCY and 80% in high dose IVCY; treatment failure defined as a composite of free of corticosteroid resistant flare, nephrotic syndrome, doubling creatinine, and persistent elevated creatinine). Low dose IVCY and high dose IVCY induction were associated with low incidence of sustained amenorrhea (4% in each group) and severe infections (11% in low dose and 22% in high dose IVCY induction). Of interest, most of the severe infection episodes occurred while patients were receiving IVCY induction. Finally an Asian study demonstrated that patients with proliferative lupus nephritis could be effectively treated with short-term oral CY induction followed by AZA maintenance. The cumulative probability of complete remission was 76%. The relapse rate was only 11%. The incidence of permanent amenorrhea and infection were 8% and 33%, respectively. None of the Asian patients had an increase in serum creatinine level to double the baseline value. Maintenance therapies with MMF or AZA following short-term CY induction in a sequential regimen are efficacious and safe for the treatment of high-risk patients with proliferative lupus nephritis.

Antineutrophil cytoplasmic antibodies: major autoantigens, pathophysiology, and disease associations.

Antineutrophil cytoplasmic antibodies (ANCA) are important serological markers for the primary systemic vasculitides, including microscopic polyarteritis and necrotizing crescentic glomerulonephritis. Numerous reports have established the clinical utility of ANCA titer in monitoring disease activity, relapses, and response to treatment. ANCA, detected by indirect immunofluorescence (IIF) assays using patient's serum and ethanol-fixed human neutrophils, produce two common fluorescent staining patterns: cytoplasmic (C-ANCA), involving a 29-kD neutral serine protease termed proteinase 3 (PR3), and perinuclear (P-ANCA), the result mainly of myeloperoxidase (MPO), but occasionally by other components of the azurophilic granules including lysozyme, elastase, cathepsins, and lactoferrin. Some sera contain granulocyte-specific antinuclear antibodies (GS-ANA), which require formaldehyde fixation of neutrophils to cross link cytoplasmic antigens for distinguishing between ANCA and the GS-ANA by IIF. Positive IIF is confirmed by Western blot analysis or specific enzyme-linked immunosorbent assay for PR3, MPO, and other neutrophil granule antigens. The C-ANCA pattern is highly specific for Wegener's granulomatosis, a disease characterized by granulomatous inflammation, necrotizing and crescentic glomerulonephritis, and vasculitis; P-ANCA is found in sera of individuals with vasculitis, glomerulonephritis, and several other diseases. ANCA are predominantly immunoglobulin (Ig)G isotype, but may be IgM and IgA. Various pathophysiologic mechanisms have been proposed involving ANCA-mediated neutrophil activation in a hypothetical model of vasculitic diseases: positive signals via the FcgammaRII (CD32) receptor after IgG-ANCA binding to membrane-associated PR3, relevant cytokines, production of adhesion molecules on both activated neutrophils and endothelial cells, and the release of neutrophil reactive oxygen species and degranulation causing endothelial cell damage. Interference of C-ANCA with PR3 proteolysis and PR3 inhibition physiologically by the alpha1-proteinase inhibitor may have a pathogenic role. No convincing data have been reported for the existence of autoreactive T lymphocytes reactive to any degree with the neutrophil azurophilic enzymes. Studies of various drug- and infectious agent-related diseases and ANCA may contribute to understanding the mechanism(s) involved in some vasculitides.

Hematologic disorders in rheumatic diseases.

Hematologic diseases often have musculoskeletal manifestations, and their diagnosis and treatment are relevant to the rheumatologist. Primary disorders of the blood such as hemophilia or sickle-cell disease may affect bones, joints, or soft tissues. Recent clinical, epidemiologic, and radiographic studies are reviewed.

13-cis-retinoic acid affects oxidation and DNA damage in oxidative-positive SLE lymphocytes but may not be useful for therapy.

13-cis-Retinoic acid (13-CRA), a water-soluble vitamin A analog and 5'-lipoxygenase inhibitor, was tested in vitro for effects on excess oxidative metabolism and DNA damage in mitogen-stimulated lymphocytes from patients with systemic lupus erythematosus (SLE), because other 5'-lipoxygenase enzyme inhibitors were shown to lower the excess oxidative metabolism in SLE cells. Excess chemiluminescence (CL) was abolished within minutes after the addition of 1 x 10(-6) M 13-CRA in five of five CL-positive mitogen-stimulated SLE lymphocytes, and was lowered in five of eight samples after 48 to 72 h culture. Similarly, low concentrations of 13-CRA for 48-72 h largely prevented the S1 nuclease-sensitive DNA changes/DNA damage observed in CL-positive lupus lymphocytes in vitro. However, 13-CRA did not affect DNA damage in four of four CL-negative lymphocyte samples. 13-CRA, like other retinoic acid compounds, was known to stimulate B-cell activities in vivo and in vitro but effects on dividing lupus T cells had not been studied. 13-CRA further inhibited the diminished PHA-stimulated lupus T-cell growth in tissue culture at a concentration of 9 x 10(-6) M in three of five lupus lymphocyte samples. 13-CRA has positive and negative effects on multiple aspects of the immune system and it is not clear whether 13-CRA will have positive or adverse clinical effects on SLE patients. Close attention to vitamin A and vitamin "supplements" in patients with SLE may answer this question.

Sickle-cell disease, hemophilia, and hematology.

Primary hematologic disorders and the hematologic problems associated with systemic rheumatologic disease have widespread and significant implications for the clinical management of rheumatic disease. This article reviews recently published information on the epidemiology, pathophysiology, and management of hemoglobinopathies, hemophilia, and other hematologic pathologies associated with significant rheumatologic manifestations.

Nonneoplastic hematologic disease.

Recent literature on nonneoplastic hematologic disease in the rheumatic disorders has been reviewed, and current concepts on the anemia of rheumatoid arthritis and its treatment have been expanded. The anemia of chronic renal failure and of acquired immunodeficiency syndrome has responded to treatment with recombinant human erythropoietin. Recent studies document that the anemia of rheumatoid disease can also be alleviated with intermittent intravenous or subcutaneous administration of erythropoietin without apparent adverse reaction. However, no improvement is evident in the underlying rheumatoid disease or functional abilities of these patients. Further data are needed to determine the utility of erythropoietin therapy in rheumatoid arthritis and in other rheumatic diseases. Other mechanisms of anemia of rheumatoid disease have been studied, and as the underlying defects become known, other therapies may become available to patients with rheumatoid arthritis and other rheumatic diseases.

Paracentral rheumatoid corneal ulceration. Clinical features and cyclosporine therapy.

Six patients with rheumatoid arthritis (eight eyes) presented with small paracentral perforating corneal ulcers in otherwise quiet eyes. Initial management in five patients (seven eyes) consisted of systemic immunosuppression and therapeutic tissue adhesive with a bandage contact lens or tectonic keratoplasty. Ulceration recurred in all of these eyes, and recurrent ulcers treated with repeat tectonic keratoplasty or therapeutic tissue adhesive and a bandage contact lens all developed recurrent ulceration. The introduction of topical cyclosporine therapy in five eyes with recurrent corneal ulceration was associated with arrest of keratolysis and rapid re-epithelialization of the ulcer in all cases. One corneal ulcer was successfully treated initially with topical cyclosporine, tissue adhesive, and a bandage contact lens. In patients with rheumatoid arthritis and small paracentral corneal ulcerations or perforations, application of tissue adhesive and a bandage contact lens and introduction of topical cyclosporine may be the preferred initial treatment.

Sarcoidosis: clinical manifestations, epidemiology, therapy, and pathophysiology.

Sarcoidosis is an idiopathic granulomatous disease involving one or more multiple organ systems, characterized by the histologic finding of noncaseating epithelioid cell granulomas. The disease has a predilection for intrathoracic structures; the musculoskeletal system is less frequently involved. Most osseous lesions in sarcoidosis are visible in the small joints of the hands and feet. Articular disease may present as an acute or chronic polyarthritis. Muscle involvement in sarcoidosis is generally asymptomatic. Neurologic findings of the central and peripheral nervous systems may occur in sarcoidosis. Subcutaneous nodules are of diagnostic value. Sarcoid vasculitis may involve small and large blood vessels. Sarcoidosis of the exocrine glands may mimic Sjögren's syndrome. Spontaneous remission of disease often occurs. Treatment with nonsteroidal anti-inflammatory agents, corticosteroids, antimalarials, radiation therapy, and immune-modulating drugs may be beneficial in the treatment of sarcoidosis.

Scavengers of free radical oxygen affect the generation of low molecular weight DNA in stimulated lymphocytes from patients with systemic lupus erythematosus.

Factors that potentially affect the generation of excess low molecular weight DNA (LMW-DNA) in cultured phytohemagglutinin (PHA)-stimulated lymphocytes of patients with systemic lupus erythematosus (SLE) were studied because this species of DNA is consistently found and this DNA may play a role in the pathogenesis of the disease. Superoxide dismutase (SOD; 0.05 mg/mL), a scavenger of free radical oxygen, decrease LMW-DNA formation in lymphocytes by 22%. Co-cultivation with cysteamine, a second scavenger of free radical oxygen and a sulfhydryl radioprotective agent, resulted in a 32% decrease in the generation of excess LMW-DNA at a concentration of 0.5 x 10(-3) mol/L and largely prevented its formation at 1.0 x 10(-3) mol/L. Other free radical scavengers (catalase, mannitol, vitamins C and E), cyclooxygenase inhibitors (ibuprofen and aspirin), a xanthine oxidase inhibitor (allopurinol), and an iron chelator (desferoxamine) did not affect excess LMW-DNA formation. Glutathione (1 x 10(-3) mol/L) had no effect and cysteine was toxic. Because scavengers of free radicals might be useful in the therapy of lupus, a trial of cysteamine (30 to 60 mg/kg/d) was administered to six acutely ill patients with SLE. A therapeutic benefit was not demonstrated, and some patients had exacerbation of disease. Lymphocyte cell growth from control and lupus subjects was stimulated when cysteamine, 1 x 10(-5) to 1 x 10(-4) mol/L was added to the media, but inhibited at concentrations of 2 x 10(-4) mol/L or greater. These studies suggest that the autooxidation and toxicity of high-dose cysteamine preclude its therapeutic use as a free radical scavenger.

Adverse reactions with oral and parenteral gold preparations.

Auranofin (triethylphosphine gold), an oral gold preparation, has recently been made available, and along with injectable gold preparations, is of therapeutic value for rheumatoid arthritis. Serious gold toxicity is uncommon, and drug-related deaths rare. Many potential adverse reactions are similar, including dermatitis, stomatitis, thrombocytopenia, leucopenia, and proteinuria, generally with increased incidence in the injectable gold-treated patients. Oral gold is associated with benign lower gastrointestinal side effects, including diarrhoea, loose stools and abdominal cramps that are often dose-related and resolve spontaneously. The incidence of severe reactions such as thrombocytopenia, aplastic anaemia and exfoliative dermatitis is lower with oral gold than injectable preparations, and contributes to a superior risk-benefit ratio. The treatment of gold toxicity depends on the type and extent of organ involvement.

The lupus activity criteria count (LACC).

A single clinical and laboratory assessment from each of 50 randomly chosen patients with systemic lupus erythematosus followed in a prospective study were evaluated for disease activity by 3 individual rheumatologists. Of the 50 assessments, 24 were considered to be active, 12 possibly active and 14 inactive. The 38 assessments that were clearly active or inactive were then analyzed. Clusters of variables were chosen for clinical relevance and association with activity, and 7 highly associated variables were combined into the lupus activity criteria count. Analysis of these criteria in the 50 assessments revealed that the presence of any 2 correctly predicted active disease in 100% of cases. This activity criteria count was then validated using a second sample of 50 assessments.

Chronic adhesive lupus serositis as a complication of systemic lupus erythematosus. Refractory chest pain and small-bowel obstruction.

Serious clinical sequelae of lupus serositis are uncommon and rarely a cause of morbidity. We describe two patients, one with chronic adhesive pericarditis and one with extensive small-bowel adhesions due to lupus peritonitis. In both, delayed institution of adequate prednisone therapy may have played a contributing role.

Immune-mediated thrombocytopenia of malaria.

Thrombocytopenia frequently complicates malarial infections but the mechanism has not been elucidated. We studied 28 patients with malarial infections and noted that 16 of 17 thrombocytopenic patients had elevated levels of platelet-associated IgG (PAIgG). In all thrombocytopenic patients studied, the level of PAIgG returned to normal as the platelet count rose to normal levels. To study the mechanism of the elevated platelet-bound IgG, IgG and F(ab')2 from patients with recurrent Plasmodium falciparum infections was purified and radiolabeled. Labeled and unlabeled P. falciparum antigen was also prepared. IgG did not nonspecifically bind to malaria-damaged platelets. Binding studies with 3H-malarial antigen demonstrated platelets have saturable binding sites for malarial antigen. Increasing concentrations of malarial antigen displaced the 125I-IgG antimalarial antibody from the platelets. The binding of 125I-IgG and 125I-F(ab')2 was similar and this excluded significant immune complex binding. The thrombocytopenia that complicates at least some malarial infections is caused by immune mechanisms; specific IgG binds to platelet-bound malaria antigen through the Fab portion of the immunoglobulin molecule.

Haemostatic abnormalities in systemic lupus erythematosus.

Coagulation studies were performed in 112 consecutive patients with systemic lupus erythematosus (SLE). Abnormalities of haemostatic function occurred frequently and 96 abnormalities occurred in 64 of 112 (57 per cent) patients. Eighteen patients (16 per cent) had thrombocytopenia, 19 (16.9 per cent) had circulating anticoagulants and 24 had decreased antithrombin III levels. Abnormalities of fibrinogen were found in 28 patients (23 per cent), and abnormalities of platelet factor 3 and 4, indicating in vivo platelet activation occurred in seven patients. In 25 patients two or more abnormalities were detected simultaneously. No haemostatic abnormalities were detected in any of the 50 healthy volunteers who served as controls. Only one patient with thrombocytopenia had petechiae. None of the other patients, even those with multiple defects bled significantly, but several patients had vasculitis and/or phlebitis. There was no correlation between disease activity of SLE and the presence of haemostatic abnormalities, nor was there an association between these abnormalities and specific clinical haematologic manifestations.

Prolonged complete remission in previously severe SLE.

Of 160 patients with systemic lupus erythematosus followed up in a long-term prospective study 4 with previously severe disease are in complete remission and have required no therapy for a median time of 75 months. The 4 females all presented with systemic features and a typical butterfly rash prompting early diagnosis and treatment. All patients have had complete remission of clinical and laboratory features of disease, without maintenance suppressive therapy.

The development and application of a serum assay for platelet-bindable IgG (S-PBIgG).

Direct assays for PAIgG are useful in diagnosing ITP and investigating mechanisms of thrombocytopenia. A serum assay for S-PBIgG would offer technical advantages in transportation and storage of samples and could prove useful in the diagnosis of thrombocytopenia caused by alloantibodies. We report the development of an assay for S-PBIgG that is positive in the majority of patients with immune thrombocytopenia. This was accomplished by empirically testing a number of variables, including the anticoagulant used to prepare target platelet, the presence of a fixative, incubation time, and the target platelet count. The development of this assay was facilitated by using a microtiter modification of the antiglobulin consumption assay, which was validated by simultaneously determining PAIgG with each method (r = 0.91, p less than 0.01, n = 42). The serum assay was then applied to the study of several types of immune thrombocytopenia PAIgG and S-PBIgG were simultaneously quantitated on platelets and sera obtained from 42 patients with idiopathic thrombocytopenia. PAIgG was elevated in 38 and S-PBIgG elevated in 34. Eleven patients had a normal or only moderately elevated S-PBIgG but a considerably elevated PAIgG. In these patients the unbound platelet antibody or immune complex may have platelet specificity. In the remaining patients there was a close correlation between the level of PAIgG and S-PBIgG (r = 0.81, n = 31) indicating that the bound platelet antibody or immune complex is dynamic equilibrium with the unbound. The potential application of the assay for S-PBIgG was demonstrated in three leukemic patients who were refractory to platelet transfusions and in two mothers who had infants with alloimmune neonatal thrombocytopenia. In these patients elevated S-PBIgG was associated with a normal or only slightly elevated PAIgG.

Systemic lupus erythematosus and pregnancy.

In a review of 250 patients with systemic lupus erythematosus (SLE), there were 24 pregnancies among 18 women. Of these, there were 16 completed pregnancies, 1 stillbirth, 1 spontaneous abortion, and 6 therapeutic abortions. Fetal loss, excluding therapeutic abortion, was 16.6%. Of the 13 patients with active disease at conception, SLE remained active in 11, and became inactive in 2. Of the 11 women with inactive disease at conception, disease remained inactive in 10. Even in the cases of previously serious renal or central nervous system involvement, inactive disease at conception was not associated with disease recurrence. Such patients may attempt pregnancy with favorable prognosis for both mother and child.