Prolonged, complete remission after 2-chlorodeoxyadenosine therapy in a patient with refractory essential mixed cryoglobulinemia.

Essential mixed cryoglobulinemia is a systemic disorder in which cutaneous vasculitis and frequently glomerulonephritis are associated with cryoprecipitable serum immune complexes. Typically, the treatment regimen consists of plasmapheresis, high-dose corticosteroids, and cytotoxic chemotherapy, as well as interferon alfa for hepatitis C virus-related cryoglobulinemia. Herein we describe a man with progressive, symptomatic cryoglobulinemia and multisystem organ dysfunction in whom corticosteroid and alkylating therapy failed; however, he had a complete and long-lasting remission after administration of 2-chlorodeoxyadenosine (cladribine).

A systematic approach to disorders of the cervical spine.

Pain in the neck may arise from a clear-cut cause (e.g., an auto accident) or without warning or apparent reason. It may limit exercise, preclude driving, or interfere with sleep, and at its worst make any movement excruciating. Common denominators are rare, although age is often a fundamental factor. It is usually best to begin management conservatively.

Atlantoaxial lateral mass osteoarthritis. A frequently overlooked cause of severe occipitocervical pain.

Localized C1-C2 lateral mass osteoarthritis is a degenerative disorder of the upper cervical spine that has a natural history markedly different from that of degenerative afflictions of the lower cervical spine. Atlantoaxial lateral mass arthritis is a distinct cause of occasionally severe occipitocervical pain in elderly persons. In this series, the diagnosis was suggested by the medical history of nine elderly patients who presented with severe occipitocervical pain (frequently diagnosed as occipital neuralgia). Physical examination demonstrated marked restriction of rotation of the cervical spine to the affected side, and localized tenderness unilaterally at the occipitocervical junction. The diagnosis was confirmed by plain radiographs of the C1-C2 articulation (open-mouth view), demonstrating marked, usually unilateral joint-space narrowing, osteophyte formation, and subchondral sclerosis. Bone scanning demonstrated focal uptake unilaterally at the occipitocervical junction. Additional imaging studies, including computed tomography, magnetic resonance imaging, or cervical myelogram, were performed to rule out coexisting intraspinal pathology. Conservative treatment was usually successful; however, C1-C2 arthrodesis was successful for severe occipitocervical pain due to atlantoaxial lateral mass arthritis not responsive to conservative treatment.

Autoantibodies to native myeloperoxidase in patients with pulmonary hemorrhage and acute renal failure.

Sera from 245 patients were screened by indirect immunofluorescence for perinuclear/nuclear staining (P-ANCA) of ethanol-fixed neutrophils, a staining pattern which is associated with the presence of antibodies to myeloperoxidase. Using immunoblot and immunoprecipitation techniques on 15 P-ANCA-positive sera, 13 patients demonstrated antibody to purified or native myeloperoxidase but not to denatured myeloperoxidase. In patients with P-ANCA, the most frequent reason for medical attention was hemoptysis (8/13; 62%). Of the 15 sera with P-ANCA, acute renal failure was identified in 9 patients (60%). Five patients (33%) had both. All patients (eight of eight) with hemoptysis had antibodies which bound functional MPO as compared to three of seven P-ANCA-positive patients without hemoptysis (P less than 0.001), suggesting that antibodies which recognize conformational sites on native myeloperoxidase occur in a subgroup of patients with alveolar hemorrhage as their presenting clinical sign. These findings may provide insight into the disease process associated with P-ANCA. We further identify a subgroup of patients with a severe pulmonorenal syndrome and antibodies recognizing native myeloperoxidase.

Extraspinal causes of lumbosacral radiculopathy.

Twelve of 12,125 patients who had been referred during a seven-year period to a specialist in spinal disorders were found to have an extraspinal cause of radiculopathy or neuropathy of the lower extremity. The records of these twelve patients were reviewed retrospectively. The average age of the twelve patients was sixty-five years (range, forty-two to seventy-seven years). The cause of the symptoms was an occult malignant tumor in nine patients and a hematoma, an aneurysm of the obturator artery, or a neurilemoma of the sciatic nerve in the others. The average time from the onset of symptoms to the final diagnosis was eight months (range, one month to two years). The most useful test for determination of the correct diagnosis was computed tomography or magnetic resonance imaging of the abdomen and pelvis. Computed tomography or magnetic resonance imaging of the spine and bone-scanning of the whole body were of little help in localizing the disease. In four of the twelve patients, an operation was performed on the basis of an incorrect diagnosis. In dealing with elderly patients who have radiculopathy, one should be suspicious that the cause is outside the spine.

Radiating leg pain in the older patient.

Failure to recognize the presentation frequently leads to misdiagnoses and treatment errors. To avoid such pitfalls, guidelines on seven prominent etiologies are provided. With careful attention to the history and physical examination, an understanding of how those etiologies present will lead to accurate diagnosis and appropriate treatment.

The value of bupivicaine hip injection in the differentiation of coxarthrosis from lower extremity neuropathy.

A series of 18 consecutive patients with roentgenographically proven osteoarthrosis (osteoarthritis, OA) of the hip and spine were evaluated because of concomitant lower extremity pain below the knee. To determine whether the leg symptoms were coxalgic or neuropathic, intraarticular hip bupivicaine was injected as a provocative test. This test allowed correct identification of the source of the pain with a sensitivity of 87%, a specificity of 100%, and an efficiency of 88%. This office test also provides significant savings in terms of diagnostic tests and patient discomfort.

Potent toxicity of 2-chlorodeoxyadenosine toward human monocytes in vitro and in vivo. A novel approach to immunosuppressive therapy.

Lymphoid cells were thought to be uniquely susceptible to excess 2'-deoxyadenosine (dAdo), when exposed to inhibitors of adenosine deaminase (ADA). However, we now find that human monocytes are as sensitive as lymphocytes to dAdo or to the ADA-resistant congener 2-chloro-2'-deoxyadenosine (CldAdo). Monocytes exposed in vitro to CldAdo, or to dAdo plus deoxycoformycin rapidly developed DNA strand breaks. Both the DNA damage and the toxicity of CldAdo or dAdo toward monocytes were blocked by deoxycytidine, but not by inhibitors of poly(ADP-ribose) polymerase. A partial decrease in RNA synthesis and a gradual decline of cellular NAD were early biochemical events associated with monocyte DNA damage. Low CldAdo concentrations (5-20 nM) inhibited monocyte phagocytosis and reduced the release of interleukin 6. Higher CldAdo concentrations led to a dose- and time-dependent loss of monocyte viability. Circulating monocytes disappeared within 1 wk in patients with cutaneous T cell lymphoma or with rheumatoid arthritis during continuous CldAdo infusion. The marked sensitivity of human monocyte function and survival to CldAdo in vitro, together with the monocyte depletion in patients receiving CldAdo chemotherapy, suggests that CldAdo or other dAdo analogues offer a novel therapeutic strategy for chronic inflammatory and autoimmune diseases characterized by inappropriate monocyte deployment or function.

Complement levels in patients with hepatic dysfunction.

Total hemolytic complement activity and serum complement protein concentrations were compared in 17 hospitalized patients with normal hepatic function and 16 patients with liver disease due to alcohol (15 patients) or acetaminophen toxicity (one patient). In contrast to the control patients, individuals with hepatic dysfunction had decreased total CH50 levels and low concentrations of total C3, C4, C5, factor B, and the regulatory proteins factor I and beta-1H. These patients also had increased C4d/C4 ratios, indicating classical pathway activation. The level of complement deficiency appears to correlate with either prolongation of the prothrombin time or depression of serum albumin concentration. These results indicate that patients with hepatic disease have severe complement depletion that is probably multifactorial in origin. This impairment in complement function will contribute to the impaired antibacterial host defense of the patient with chronic hepatic disease.

The clinical significance of iC3b neoantigen expression in plasma from patients with systemic lupus erythematosus.

We studied the expression of an iC3b neoantigen (iC3b-NEO) in plasma from patients with systemic lupus erythematosus (SLE), by using a monoclonal antibody specific for iC3b/C3dg/C3d, to investigate the activation of the third component of complement in SLE. The plasma iC3b-NEO level in 40 untreated patients with active SLE was significantly higher than that in 36 normal subjects (mean +/- SD 31.5 +/- 13.9 micrograms/ml versus 12.3 +/- 3.3 micrograms/ml; P less than 0.001). The plasma iC3b-NEO level was highly correlated with clinical disease activity (tau = 0.62, P less than 0.0001), and it was the parameter most closely correlated with renal histologic activity in lupus nephritis (tau = 0.52, P less than 0.0001). Also, patients with diffuse proliferative lupus nephritis had the highest levels of plasma iC3b-NEO among all World Health Organization classes of lupus nephritis (P less than 0.01). We conclude that the plasma iC3b-NEO level is strongly associated with clinical disease activity and renal histologic activity in patients with SLE, and that plasma iC3b-NEO may be a sensitive and useful measure of complement activation in SLE.

Diagnosis and management of lumbar disk disease.

Management of the patient with low back pain need not be particularly confusing, expensive, or invasive. A systematic approach to categorizing this ubiquitous symptom etiologically, followed by appropriate choice of diagnostic imaging techniques and an individualized treatment program, will heighten cost-effectiveness and sharply reduce the demand for surgical intervention.

High-molecular-weight kininogen is cleaved in active erythema multiforme.

Erythema multiforme (EM) is an inflammatory disorder of the skin, which may include mucous membrane involvement, that features target (iris) lesions. Mediators specifically involved in EM are not well characterized; its pathogenesis remains enigmatic. In this study, evidence for participation of kinins in the pathophysiology of inflammation in EM was investigated by assessing cleavage of high-molecular-weight kininogen (HMWK) in plasma. These data were compared with analyses of plasmas from patients with serum sickness, chronic idiopathic urticaria/angioedema, and from normal control subjects. Patients with EM demonstrated significant levels of circulating cleaved HMWK in plasma during active disease (p less than 0.01), which declined during remission/recovery. Plasmas from patients with EM obtained during active disease also demonstrated significant levels of 94 kd C1 inhibitor (p less than 0.01) and C1 inhibitor-kallikrein complexes. Patients with serum sickness and chronic idiopathic urticaria/angioedema did not demonstrate these findings and did not differ from normal control subjects (p = not significant). Although the kininogenase responsible for HMWK cleavage in EM has not been conclusively demonstrated, these findings suggest that HMWK cleavage resulted from activation of the contact system and that some of the manifestations of EM in selected patients may in part be accounted for by inflammatory and proinflammatory actions of kinins. Based on these preliminary findings, it will be important to establish whether or not HMWK cleavage in EM is a general finding in patients with this disorder. Further investigation is needed to characterize more clearly kininogenase activity and elucidate the possible role of kinin generation in EM.

Detection and quantitation of cleaved and uncleaved high molecular weight kininogen in plasma by ligand blotting with radiolabeled plasma prekallikrein or factor XI.

A method for the quantitative assay of native single chain and kallikrein cleaved two-chain high molecular weight (HMW)-kininogen in plasma is described. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of whole plasma is followed by electrotransfer of the electropherogram to nitrocellulose membranes and detection of the blotted HMW-kininogen with its physiologic ligands, radiolabeled plasma prekallikrein or radiolabeled factor XI. Using unreduced SDS-PAGE cleaved two-chain HMW-kininogen (Mr approximately 107,000 and 95,000), is electrophoretically separated from uncleaved single chain HMW-kininogen (Mr approximately 150,000). Counting the radioactivity of the nitrocellulose pieces corresponding to cleaved HMW-kininogen permits its quantitative measurement by comparison with standards consisting of decreasing amounts of fully dextran sulfate activated normal human plasma. Single chain HMW-kininogen is similarly assayed using reduced SDS-PAGE and unactivated normal human plasma standards. This technique is highly specific and sensitive to about 50 ng of either cleaved or uncleaved HMW-kininogen. Varying amounts of cleaved HMW-kininogen were found in a small series of plasmas from patients suffering from various inflammatory conditions. Higher levels of in vivo cleaved HMW-kininogen were observed during acute attacks of hereditary angioedema due to Cl-inhibitor deficiency. This technique may be useful for the assessment of the degree of in vitro or in vivo activation of the contact system.

Complement profiles in acute post-streptococcal glomerulonephritis.

It is well known that the hypocomplementemia of acute post-streptococcal glomerulonephritis (APSGN) is characterized by markedly reduced serum concentrations of C3 and moderately reduced levels of C5 and properdin (P). However, the extent of the activation of the classical pathway is not well defined and only limited data are available concerning serum concentrations of terminal components other than C5. In serial serum specimens from 14 children with APSGN, the presence and extent of C4 activation was directly assessed by measurement by rocket immunoelectrophoresis for C4 and C4 (C4d/C4 ratio). Elevated values for this ratio, indicating C4 activation, were found in 8 of 14 of the initial serum specimens, and in some patients the ratio remained elevated for several weeks. In contrast, the serum C4 level was low in only 1 specimen (the specimen with the highest C4d/C4 ratio). However, in 10 patients C4 concentrations within the normal range rose in serial serum specimens. Serum C2 concentrations were depressed in the initial specimens from 5 patients. The concentrations of 13 other complement component and control proteins were also measured in these specimens. Levels of terminal components, other than C5, in the initial serum specimens were normal except for depressed C8 in 3 of 13 patients and depressed C6 in 1 of 14. Of these 4 individuals, 3 had the lowest C3 levels in the study. It is concluded that the classical complement pathway is frequently activated in patients with APSGN early in the condition and that subtle abnormalities in C6 and C8 levels occasionally occur.

Underlying complement deficiency in patients with disseminated gonococcal infection.

The complement system was evaluated in 22 individuals with disseminated gonococcal infection. Three of the 22 patients exhibited a total serum complement activity that was greater than 2 SD below the normal mean. Of these three, one had a complete deficiency of C1r, a second patient had pre-existing systemic lupus erythematosus with low levels of C4, and the third had a C8 concentration that was 60% of normal. We conclude that the prevalence of inherited or acquired complement deficiency among patients with disseminated gonococcal infection exceeds that among the general population and is an important host factor predisposing to systemic infection with Neisseria gonorrhoeae.

Complement activation in IgA nephropathy.

Activation of alternative complement pathway is presumed to be important pathogenically in IgA nephropathy since renal biopsies usually exhibit glomerular deposition of C3 and P (properdin). Surprisingly, little is known about plasma complement activation in this disease, and the plasma C3 and C4 concentrations are usually normal or increased. We quantitated C3 activation in 202 plasmas from 81 patients with IgA nephropathy using a sensitive new assay that detects a neoantigen [iC3b-C3d neoantigen) which appears when C3b is inactivated to iC3b, C3dg, or C3d. This assay accurately quantitates small amounts of in vivo C3 activation. The concentration of iC3b-C3d neoantigen in plasma was significantly increased, indicating C3 activation in 37% of the pediatric and 57% of the adult plasmas assayed. When data from serial determinations in the patients were analyzed, 75% of the adult and 57% of the pediatric patients had C3 activation on at least one occasion. Classical pathway activation, quantitated by C4 activation was found in 20% of the adult and 5% of the pediatric plasmas. No association was found between elevated iC3b-C3d neoantigen concentration and history of macroscopic hematuria, chronic renal insufficiency or degree of proteinuria. These studies show that complement activation can frequently be detected in the plasma of IgA nephropathy patients. However, the pathophysiologic significance of this complement activation remains to be determined.

Effects of recombinant human interferons on rheumatoid arthritis B lymphocytes activated by Epstein-Barr virus.

We evaluated the effects of all 3 classes of recombinant human interferon (IFN) on Epstein-Barr virus (EBV) infection of purified B lymphocytes from patients with rheumatoid arthritis (RA). After EBV infection, RA B cells secreted more IgM and significantly more IgM rheumatoid factor (RF) than normals. Spontaneous (no EBV) proliferation, IgM, and IgM RF were also higher in RA. All 3 types of IFN inhibited dose dependently EBV induced B cell activation. In RA, however, higher doses of each class of IFN were necessary to obtain 50% inhibition. IFN gamma was most potent in normals and RA. Four IgM RF production IFN gamma was significantly more potent than IFN alpha and IFN beta in reducing the spontaneous activation of RA B cells, and a similar trend was seen in B cell proliferation. These findings are discussed in the context of ongoing clinical trials with IFN gamma in RA.