Selden Longley

Vasculitis associated with malignancy. Experience with 13 patients and literature review.

Vasculitis is a syndrome which may complicate certain infectious, rheumatic, and allergic diseases. We identified 13 patients, over the past 17 years, who had both vasculitis and lympho- or myeloproliferative disorders and relate their clinical, laboratory, histologic, and immunologic features, course, therapy, and outcome. Nine patients were male, 4 female; ages ranged from 28 to 82 years. Ten of 13 patients presented with cutaneous vasculitis antedating malignancy by an average of 10 months. Three of 13 developed cutaneous vasculitis after malignancy. A statistically significant association between cutaneous vasculitis and lympho- or myeloproliferative malignancies was noted when compared with all other tumors. Dermatologic manifestations included palpable purpura (5 patients), maculopapular eruptions (4), urticarial and petechial lesions (3), and ulcers (1). Hepatitis B surface antigen, Coombs antibodies, rheumatoid factor and antinuclear antibodies were not found. Serum cryoglobulins were detected in 3 patients; serum C3 and C4 were normal in 8 of 9 patients evaluated. Histologic examinations revealed necrotizing leukocytoclastic vasculitis with disruption of endothelial integrity, destruction of endothelium, and neutrophil infiltration. Occasional perivascular mononuclear cell invasion was also noted in 4 patients. Immunofluorescent staining for IgG, IgA, IgM, C3, and C4 was negative in all patients studied. Symptoms were, in general, poorly responsive to therapy, which included nonsteroidal antiinflammatory drugs, antihistamines, antiserotonin agents, and corticosteroids. Chemotherapy directed at the underlying malignancy was also generally ineffective, although the vasculitis appeared to lessen in severity. Vasculitis appeared to lessen in severity as bone marrow function deteriorated. Ten patients died, all as a direct result of their malignancy. We have described a unique clinical syndrome of lympho- and myeloproliferative disease presenting with small-vessel vasculitis. Recognition that rheumatic symptoms may reflect or antedate malignancy may permit early diagnosis, aggressive treatment, and elucidation of pathogenesis.

Paraneoplastic vasculitis. Unique syndrome of cutaneous angiitis and arthritis associated with myeloproliferative disorders

Six patients are described whose myeloproliferative disorders were complicated by inflammation in small, predominantly cutaneous blood vessels. The clinical manifestations of the vasculitis included palpable purpura, urticaria, maculopapular lesions, and erythema multiforme. Vascular inflammation was confirmed by skin biopsy. Two patients experienced fleeting, asymmetrical nondestructive arthritis. Transient proteinuria complicated one case and was the only suggestion of visceral vasculitis. The clinical features of cutaneous vasculitis antedated bone marrow deterioration in four patients and diminished as bone marrow function worsened in all patients. Oral corticosteroids or chemotherapy for the underlying disorder inconsistently affected the clinical course of the cutaneous vasculitis. Myeloproliferative disorders should be considered among disorders that are complicated by inflammation in small blood vessels.

Weber–christian Disease: Analysis Of 15 Cases And Review Of The Literature

We report 15 patients encountered over 13 years who presented with inflammation of subcutaneous fat and were given clinical and pathologic diagnoses of Weber--Christian disease (WCD). Prominent clinical features included female predominance, lower extremity nodules, fevers, arthritis/arthralgias, and myalgias. Notable laboratory features were elevated erythrocyte sedimentation rate, anemia, leukopenia, and hypocomplementemia, frequently with circulating 7S IgM or immune complexes at times of active symptoms. Histologic findings were lobular--together with frequent septal--panniculitis, fat-laden macrophages, variable cellular infiltrates, necrosis, and occasional vasculitis. Follow-up revealed the death of 2 patients and disease stabilization or improvement in 13 patients. Six patients developed features of other diseases (factitial disease, erythema nodosum, acute myelogenous leukemia, rheumatoid arthritis, systemic lupus erythematosus, and sarcoid) and a seventh may have had erythema induratum. We suggest that classic WCD, as originally described, reflects an increasingly recognized spectrum of panniculitides. These are syndromes of diverse etiology that share many clinical, inflammatory, and immunologic features.

Scleroderma esophagus: A nonspecific entity

Abstract Esophageal dysfunction develops in approximately 90% of patients with progressive systemic sclerosis (scleroderma) or mixed connective tissue disease (1). Abnormal esophageal motility may ...

Rheumatoid vasculitis: diagnostic and therapeutic decisions

SummaryRheumatoid vasculitis is an uncommon but potentially catastrophic complication of RA. There are few extensive experiences recorded in the current literature and there is no consensus regarding the clinical features, laboratory findings, histologic pattern, prognosis, or appropriate management of this syndrome. We therefore surveyed 1,947 North American ARA members for their perceptions of rheumatoid vasculitis. Fourhundred twenty-eight surveys were returned, of which 290 were suitable for analysis. The majority of respondents were within 10 years of fellowships and were even distributed among private practice, and parttime and full-time academic positions. The respondents saw 15–50 rheumatoid arthritis (RA) patients weekly and less than five RA vasculitis patients annually. The majority correctly diagnosed two actual and complex case histories from patients with and without autopsy-proven vasculitis. Respondents associated the following features most strongly with rheumatoid vasculitis — mononeuritis multiplex, digital gangrene, digital ischemic lesions, nailfold ischemic lesions, non-healing leg ulcers, palpable purpura, fingertip nodules, sensory neuropathy, scleromalacia perforans, high titer rheumatoid factor, positive visceral angiography, cryoglobulinemia, hypocomplementemia, circulating immune complexes, and histologic necrotizing vasculitis or vascular transmural neutrophilia. Digital lesions or sensory neuropathy alone were not viewed as portending an ominous prognosis by most respondents and would have been treated with nonsteroidal anti-inflammatory drugs, antimalarials, gold salts, or D-penicillamine. Other clinical manifestations considered as reflecting rheumatoid vasculitis (gangrene, mononeuritis multiplex, ulcers) were thought to worsen prognosis and would have been managed more often with corticosteroids, D-penicillamine, cytotoxic agents or plasmapheresis. Rheumatoid vasculitis is viewed as a heterogeneous group of syndromes with varying clinical and histopathologic features, which have different prognostic implications, and therefore should be managed differently. While these data do not substitute for an extensive recorded series of patients, they provide useful information about community perceptions of an uncommon but difficult clinical problem. They identify the need for additional data to examine the validity of these attitudes.

Magnetic resonance imaging in patients with inflammatory arthritis of the knee.

SummaryMagnetic resonance imaging (MRI) permits visualization of anatomic structures not appreciated by conventional radiographic imaging and may quantify inflammatory disease and its progression with greater sensitivity than available techniques. We therefore compared MRIwith clinical evaluation and with radiographic examination of 17 patients with inflammatory arthritis of the knee. We sought to determine anatomic integrity of bone, cartilage, menisci, and ligaments, and to quantify joint effusion and synovial proliferation. Patients studied had rheumatoid arthritis (10patients), juvenile rheumatoid arthritis (4patients), ankylosing spondylitis (1 patient), and monoarticular arthritis (2 patients). In all patients MRI revealed clinically important abnormalities not detected by physical or conventional radiographic exams. These included proliferative synovitis (13 patients), cartilage thinning (2 patients), cartilage erosion (8 patients), bone infarction (1 patient), meniscal injury (1 patient), and synovial invagination into bone (1 patient). Also MRI indicated inflammatory disease to be quantitatively greater than had been appreciated on clinical examination or routine X-ray studies-proliferative synovitis (12 patients), erosion (7 patients), effusion (8 patients), cartilage thinning (11 patients), and ligamentous/meniscal damage (1 patient). These findings led to reassessment of anatomic staging and influenced therapeutic decision for these patients. Thus MRI provides clinically important information about joint integrity and inflammatory disease, with a sensitivity and resolution considerably beyond conventional techniques.

In vitro immunoglobulin production by mononuclear cells in rheumatoid arthritis.

Since patients with rheumatoid arthritis (RA) exhibit serum hypergammaglobulinemia and autoantibody (rheumatoid factor) production, we compared elaboration and control of in vitro RA mononuclear cell (MNC), Ig assayed by enzyme-linked immunoassays or by hemolytic plaque formation, in 37 RA patients and 17 normal subjects. We found (1) RA spontaneous plaque-forming cells were significantly reduced (RA 344 vs normal 627 PFC/10(6) MNC, P less than 0.002); (2) RA spontaneous IgG and IgM (but not IgA) elaboration was significantly diminished (IgG RA 339, normal 776; IgM RA 255, normal 869 ng/ml, P less than 0.001; IgA RA 87, normal 124); (3) RA stimulated IgG and IgM production (but not IgA) was also decreased (IgG RA 2434, normal 3862, P less than 0.06; IgM RA, 1676, normal 3323, P less than 0.005; IgA RA 1859, normal 2315); (4) reduced RA Ig elaboration was not clearly due to altered numbers of T or non-T cells, age, medications, clinical features of disease, or response kinetics; (5) relative improvement of RA in vitro IgG, but not usually IgM, secretion followed removal of adherent cells, addition of indomethacin or addition of mitomycin C-treated T cells; (6) MNC from synovial fluids, but not bone marrows, exhibited spontaneous Ig production in excess of stimulated synovial fluid cellular or peripheral blood Ig elaboration. These observations indicate selective impairment of peripheral blood MNC IgG and, particularly, IgM secretion in RA. This defect appears to reflect accessory cell influences which differ from normal as well as the sequestration of primed or activated cells in the synovial fluid.

IgM rheumatoid factor elaboration by blood, bone marrow, and synovial mononuclear cells in patients with rheumatoid arthritis

IgM rheumatoid factor (RF) elaboration by rheumatoid arthritis (RA) synovial, bone marrow, and blood mononuclear cells (MNC) is reported. IgM RF was prepared from RF-positive sera by sequential euglobulin precipitation, Sephacryl S300 gel filtration, and IgG-Sepharose affinity chromatography. Purified material, which contained no detectable IgG or IgA, was used in an enzyme-linked immunosorbent assay (ELISA) to quantitate cellular elaboration of IgM RF. Excellent standard curves (r2 = 0.98) were obtained without nonspecific binding of samples or antisera to IgG-coated microtiter plates and without cross-reactivity of standards with antisera other than anti-IgM. We found RA blood MNC (11 patients) spontaneously averaged 15 ng/ml IgM RF (6% of total IgM produced), but elaborated 254 ng/ml IgM RF following pokeweed mitogen (PWM) stimulation (22 patients), exceeding that of 13 normal controls. Bone marrow MNC spontaneously (4 patients) produced 71 ng/ml IgM RF and secreted 78 ng/ml IgM RF with PWM stimulation (9 patients). In contrast synovial fluid MNC (5 patients) spontaneously elaborated 6652 ng/ml IgM RF, significantly (P less than 0.05) more than blood or bone marrow MNC; PWM-stimulated synovial fluid MNC (5 patients) produced 5472 ng/ml IgM RF. These observations confirm selective localization of activated, IgM RF-producing cells to the rheumatoid synovial space.

Detection and quantitation of circulating immune complexes in arterial blood of patients with rheumatic disease

We developed antigen-nonspecific enzyme-linked immunoassays (ELISA) to quantitate IgG-C3- and IgM-C3-containing circulating immune complexes (CIC) in venous and arterial blood from rheumatic disease patients. Standards were diethylaminoethyl (DEAE)-purified, heat-aggregated IgG incubated with fresh human serum (for IgG-C3 CIC) and IgM rheumatoid factor-rich serum incubated with reduced, alkylated IgG and then with fresh human serum (for IgM-IgG-C3 CIC). Venous serum and plasma IgG-C3 and IgM-C3 CIC correlated closely (P less than 0.01). Rheumatoid arthritis (RA) and systemic lupus erythematous (SLE) patients had elevated levels of venous IgM-C3 CIC (P less than 0.0001) but not IgG-C3 CIC; patients with vasculitis, inflammatory rheumatic diseases, or noninflammatory rheumatic diseases had mean values similar to normal individuals. Venous IgG-C3 and IgM-C3 CIC did not correlate. Paired venous and arterial samples from 16 rheumatic disease patients averaged comparable amounts of IgG-C3 and IgM-C3 CIC, respectively; venous and arterial IgM-C3 CIC levels in patients significantly exceeded normals (P less than 0.05). Venous and arterial IgG-C3 CIC levels correlated closely (P less than 0.01) as did venous and arterial IgM-C3 levels (P less than 0.05). Thus, arterial CIC offered no advantage over venous determinations for rheumatic disease patients. IgM-C3 CIC were elevated in patients with RA and SLE when IgG-C3 CIC were not. Ig isotype-specific CIC quantitation may be useful for certain rheumatic diseases.