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A patient is described in whom a recurrence of vasculitis was observed in the kidney allograft six years after transplantation and one year after withdrawal of corticosteroid therapy. This case shows that systemic vasculitis may recur at any time after transplantation which implies a continuous and careful monitoring of these patients.
The therapeutic effect of a course of high-dose, pooled, intravenous immunoglobulin (IVIg) on disease activity and circulating antineutrophil cytoplasm antibodies (ANCA) was investigated in 7 patients with systemic vasculitis. 5 had active disease despite conventional immunosuppression, and 2 had not received any treatment. All 7 had clinical improvement, which was sustained in 6 and transient in 1. The fall in ANCA concentrations to a mean of 51% of the pre-treatment values was maintained during follow-up. C-reactive protein concentration also dropped considerably. IVIg seemed to confer a useful therapeutic effect without adverse reaction.
BACKGROUND: Antineutrophil cytoplasmic autoantibodies (ANCA) are directed against antigens located in the cytoplasm of neutrophil granulocytes and monocytes. Detection of ANCA has proved to be a useful diagnostic tool for a group of systemic vasculitis, especially Wegener's granulomatosis. Both indirect immunofluorescence (IIF) and ELISA have been used to detect ANCA. MATERIAL AND METHODS: In this study, samples from 319 patients tested by both immunofluorescence and ELISA were evaluated; 27 of these were diagnosed with Wegener's granulomatosis. RESULTS: The diagnostic sensitivity for Wegener's granulomatosis was 70% for C-ANCA and 63% for PR3-ANCA. The specificity was 97% and 99% respectively. Positive predictive value for the diagnosis of Wegener's granulomatosis in our population was 68% for C-ANCA and 90% for PR3-ANCA. Negative predictive value was 97% and 97% respectively. INTERPRETATION: We recommend that immunofluorescence is used for screening when an ANCA-associated vasculitis is suspected. However, a number of antigen specificities can provide the immunofluorescence patterns, and for this reason we recommend PR3-ELISA and MPO-ELISA tests whenever the immunofluorescence test is positive.
Vasculitis has been seen in rectal biopsies from 22 patients over a six year period. The most common finding was a necrotising vasculitis of small arteries, indistinguishable from that seen in polyarteritis nodosa (PAN). Sub-acute, chronic ("burnt out") and leucocytoclastic changes were also seen. Sixteen patients had vasculitis complicating rheumatoid arthritis (RA), 3 PAN and 3 overlap syndromes. Patients with RA and rectal vasculitis had a higher mortality, and a greater incidence of neuropathy than those with negative biopsies. An adequate biopsy is positive in 40% of patients with clinical vasculitis and RA but was only positive in one of a control series of 46 RA patients with no clinical vasculitis. Rectal biopsy in experienced hands is a safe, and repeatable procedure. It is useful as a "blind" biopsy site in the diagnosis of systemic vasculitis, especially that complicating RA. It can also be used for serial studies of the evolution of vasculitis. Serial sections of the entire biopsy may be required to reveal the vasculitis which is often focal in nature.
The efficacy of cyclophosphamide (CY) in the treatment of severe systemic vasculitis has been demonstrated, but its optimal administration regimen remains to be defined. The four patients described participated in prospective therapeutic trials of polyarteritis nodosa (PAN) without hepatitis B infection markers, Churg-Strauss syndrome (CSS) and Wegener's granulomatosis (WG) and received daily oral low-dose CY after failure of a monthly pulse regimen. These patients were included in this study because of failure to induce clinical remission (two patients) and relapse during the course of treatment (two patients). The results were good with initial clinical remission in three patients and stabilization in one. One patient with WG relapsed 10 months after changing therapeutics. The advantages of the different administration protocols are discussed.
PURPOSE OF REVIEW: The role of the endothelium as an active player rather than a passive victim of inflammation has received considerable interest in atherosclerosis, but less so in systemic vasculitis (SV). However, the accumulating multi-organ damage seen in SV probably includes the endothelium. Assessment of endothelial function is now a standard clinical research tool in cardio-vascular departments. The exciting insights provided by their application to SV, in both primary disease and connective tissue diseases (CTD), is reviewed here. RECENT FINDINGS: Diffuse endothelial cell dysfunction (ECD) documented by several techniques occurs commonly in adult and childhood SV. Similar ECD is also seen in CTD. The mechanisms probably relate to inflammatory cytokines such as TNF. The particular role of vasculitic, as opposed to synovial or internal organ inflammation, may be release of secondary mediators directly into the blood stream- whence they can reach distant endothelial beds to induce this diffuse ECD. SUMMARY: Endothelial injury is the first step in atherosclerosis, where peripheral abnormalities correlate with coronary artery responses. The diffuse ECD in CTD suggests that vascular inflammation may initiate the accelerated CVS disease there. The new findings of similar ECD in primary SV predicts enhanced atherosclerosis here too. In Kawasaki syndrome, persistent late ECD correlates with abnormal coronary responses. In adult SV, initial data also suggests increased subclinical atherosclerosis. The role of endothelial function in the clinical outcome of SV deserves more attention. Research to pinpoint the mechanisms of ECD should lead to more specific therapies that may ameliorate the continuing late morbidity and mortality of SV.
This is the case of 55 year-old man, in whom Hodgkin's disease with a slight enlargement of lymphatic glands symptoms of the myasthenic syndrome and systemic vasculitis have been found. The patient's bad condition was caused by weakness and fatigability of muscular power, haemorrhagic gastritis and nephrotic syndrome. The patient was treated according to the schema of MOPP/ABV (hybrid). By now, three and a half year since the moment of treatment cessation, the patient has remained in remission. Any abnormalities have been found in electromyography, laboratory and imaging diagnostics.
We report an association of severe pulmonary hemorrhage with circulating autoantibodies to neutrophil cytoplasmic antigens (ANCA) restricted to IgM class in three patients with systemic vasculitis. ANCA were detected by indirect immunofluorescence and isotype specific solid phase radioimmunoassay (SPRIA). Institution of immunosuppressive therapy was accompanied by an isotype switch to IgG ANCA and recovery in all three patients. In an associated study, ANCA activity was found in eluates from the washed glomeruli of two postmortem cases, with the same isotype distribution as was present in the sera.
There are many different and diverse causes of central nervous system (CNS) vasculitis, and many nonvasculitic disorders that often mimic CNS vasculitis. CNS vasculitis is usually suspected clinically with compatible or suggestive angiographic findings, but a definitive diagnosis is not possible without biopsy confirmation, especially with CNS vasculitis mimickers. Primary CNS vasculitis, although relatively uncommon, is most important because of its overall unfavorable prognosis. Secondary CNS vasculitis occurs in association with a long list of systemic vasculitic and nonvasculitic disorders with variable brain biopsy findings. Because of the focal and segmental distribution of CNS vasculitis, a positive biopsy is diagnostic for the disease demonstrated, but a single isolated negative biopsy does not necessarily exclude primary or secondary CNS vasculitis.
The primary small vessel systemic vasculitides are disorders that target small blood vessels, inducing vessel wall inflammation and associated with development of antineutrophil cytoplasmic antibodies. Multiple organs are attacked including the lungs and kidneys. Increasing knowledge of pathogenesis suggests that the antibodies activate neutrophils inappropriately, leading to endothelial and vascular damage. Cytokines such as tumour necrosis factor (TNF) can facilitate the damage by priming neutrophils and activating endothelial cells. Understanding pathogenesis can help to rationalise existing therapies and indicate new approaches to therapy such as the use of agents that inhibit the effects of TNF.
Microbiology, X-ray study, and bronchoscopy, including the examination of bronchoalveolar lavage and histology of thransbronchial lung biopsy specimens have proven to be of the greatest informative value in the differential diagnosis of different forms of systemic vasculitis and tuberculosis in 52 patients. Focal pulmonary tuberculosis was detected in the phase of S(II) infiltration on the right in a patient with rheumatic arthritis; Mycobacterium tuberculosis was bacterioscopically detected. The patient underwent specific antituberculous therapy that provided beneficial effects.
The clinical and laboratory data regarding the presence of serum markers of hepatitis B virus (HBV) were studied in a group of patients with necrotizing vasculitis. A high incidence of skin and articular alterations, of cryoglobulinemia and rheumatoid factor, was observed in HBsAg carriers. The potential role of HBV in the pathogenesis of systemic vasculitis is discussed.
In a prospective study over 2 years, serum C-reactive protein (CRP) concentration and erythrocyte sedimentation rate were measured serially in thirty-eight patients with various types of necrotizing systemic vasculitis. The CRP concentration was always elevated in patients with active vasculitis and fell rapidly in association with clinical remission induced by immunosuppression. During periods of complete remission, in the absence of any intercurrent condition, the value remained within the normal range. In contrast the sedimentation rate responded more slowly to changes in disease activity and did not necessarily reflect the level of inflammation at a particular time. These results, together with the commercial availability of rapid and precise assays for CRP, indicate that serial measurement of the serum CRP fills the urgent need for an objective index of the activity of the systemic vasculitides and their response to therapy.
Eleven patients with symptoms highly suggestive of Wegener's granulomatosis are described. In spite of extensive investigation, only in two patients was a firm histological diagnosis of Wegener's granulomatosis obtained, while the remaining patients were either diagnosed as having unclassifiable systemic vasculitis or had no histological diagnosis made. This sometimes resulted in diagnostic and therapeutic delay and irreversible organ damage. Antibodies to components of neutrophil cytoplasm--recently demonstrated to be specific for Wegener's granulomatosis--were detected by indirect immunofluorescence in 10 of 11 patients, and it appears likely that antibodies to components of neutrophil cytoplasm will prove to be of great value in early diagnosis.
We report a 42-year-old man who showed alveolar hemorrhage and glomerulonephritis as well as episcleritis and skin rash. He had an extremely high titer of cytoplasm-staining antineutrophil cytoplasmic antibody (C-ANCA) and was diagnosed as having systemic vasculitis based on histological findings of kidney and skin biopsies. After immunosuppressive therapy clinical manifestations resolved within several weeks and C-ANCA titers commensurably declined. C-ANCA titers, however, increased again and remained high despite clinical remission. In general, there is a close relationship between ANCA titers and clinical activities in ANCA-associated diseases, but they displayed a large discrepancy in this patient. Indeed, the serum of the patient in remission contained the antibody against 29-kD neutrophil extracts which was detected by immunoblot analysis. These findings suggest that C-ANCA may not necessarily be, by itself, pathogenetic for the development of the vasculitis.
A 75-year-old man, previously diagnosed as having chronic hepatitis C virus (HCV) infection, suddenly developed left foot drop, followed by progressive motor weakness and sensory disturbance in all of the extremities. Because of an elevated level of the rheumatoid factor (RF), he had been treated with antirheumatic drugs three years before the onset of his neurological symptoms. Within two months, he became unable to walk any more, and was transferred to our hospital. Neurologic examination showed asymmetrical severe muscular weakness and atrophy of all the limbs, and a sensory deficit under the level of the wrists and knees. Livedo reticularis was also noted in bilateral legs. Nerve conduction study revealed severe sensorimotor axonal neuropathy, and muscle biopsy specimens showed necrotizing vasculitis of small arteries in the perimysium. Serological tests indicated type II cryoglobulinemia (monoclonal IgAkappa + polyclonal IgG). A diagnosis of vasculitic neuropathy associated with HCV-related mixed cryoglobulinemia was made. A high-dose intravenous immunoglobulin therapy (IVIg) and a high-dose steroid therapy were not effective, and he died of alveolar hemorrhage probably due to pulmonary vasculitis. Postmortem pathological examination revealed severe vasculitis, accompanied by fibrinoid degeneration and the infiltration of predominant mononuclear cells into the small and medium-sized vascular walls of multiple organs such as the liver, kidney, pancreas and intestine as well as the peripheral nerves and skeletal muscles. A severe loss of myelinated fibers were also observed in the multiple peripheral nerves examined. We emphasize that patients with HCV infection and mixed cryoglobulinemia may develop severe systemic vasculitis resembling polyarteritis nodosa leading to often life-threatening polyvisceral failure, particularly in patients showing progressive mononeuropathy multiplex.
Several recent advances in the use of immunosuppressive drugs in autoimmune disease are relevant to management of autoimmune pulmonary disease. Sequential immunosuppression combining remission induction with cyclophosphamide with less toxic maintenance therapy such as azathioprine, methotrexate, or mycophenolate mofetil is described in Wegener's granulomatosis, systemic vasculitis, and lupus. Less aggressive forms of diseases that have been routinely treated with cyclophosphamide have been treated with alternate regimens (e.g., methotrexate treatment of limited Wegener's granulomatosis, and mycophenolate mofetil for lupus). Finally, strategies to minimize severe side effects of immunosuppression include genetic testing for predisposition to drug toxicity and proposed techniques for fertility preservation during cyclophosphamide treatment. We review established principles of immunosuppressive drug use and focus on clinical trials in autoimmune diseases that illustrate therapeutic approaches which are likely to be applied more widely in the future. More detailed reviews of treatment of individual diseases will be found in elsewhere in this issue.
When cytotoxic agents were introduced, their ability to disrupt nucleic acid and protein synthesis led to their effective use for the treatment of neoplastic disease. During the course of this use, however, it became apparent that these agents also suppress the immune system. This usually unwelcome effect was subsequently studied and beneficially directed toward the treatment of non-neoplastic diseases in which autoimmune mechanisms were considered important to pathogenesis. As a result of these investigations, cytotoxic agents and, more recently, cyclosporine have emerged to become an important part of the therapeutic regimen for many autoimmune diseases. Nonetheless, these medications may still cause treatment-induced illness or even death. It is therefore particularly important to weigh the benefits and risks of cytotoxic therapy when treating a non-neoplastic disease. This two-part Clinical Staff Conference reviews data on the efficacy and toxicity of cytotoxic drugs and cyclosporine in selected autoimmune diseases. In part 2, we focus on the role of these agents in treating inflammatory bowel disease and systemic vasculitis and review the toxic effects of these agents.