Tumor-induced osteomalacia: lessons learned.

Tumor-induced osteomalacia is a rare acquired metabolic disorder characterized by hypophosphatemia and inappropriately low serum levels of 1,25-dihydroxyvitamin D. Symptoms include chronic muscle and bone pain, weakness, and fatigue in association with a high risk of fragility fractures due to osteomalacia. The diagnosis is commonly delayed for years due to the nonspecific nature of the presenting symptoms, failure to include determination of serum phosphorus levels in blood chemistry testing, and difficulty in identifying the responsible tumor. The pathogenesis of tumor-induced osteomalacia involves tumor expression of fibroblast growth factor 23, a hormone that inhibits proximal renal tubular reabsorption of phosphate and down-regulates renal conversion of 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D. The metabolic abnormalities may be partially or completely corrected with phosphate supplementation and calcitriol. A definitive diagnosis and treatment require excision of the responsible tumor.

Predominance of T cells in the lymphocytic infiltrates of synovial tissues in rheumatoid arthritis.

Synovial tissues from 5 patients with rheumatoid arthritis (RA) were examined immunofluorescence microscopy for the presence of lymphocytes with either bone marrow-derived (B) or thymus-derived (T) surface markers. Five synovial tissues with severe to mild lymphocytic infiltrations by bright field microscopy were examined in parallel with immunofluorescence. B cells were identified with a pepsin-digested fluoresceinated anti-F (ab')2 antiserum and T cells were detected with a specific rabbit and anti-T lymphocyte antiserum. By these techniques 75-90% of the lymphocytes in these frozen sections were identified as T cells. Cell suspensions were also prepared by collagenase digestion of two of the five synovial tissues. The lymphocytes in these cell suspensions were predominantly T lymphocytes (78-85%) as shown by their ability to form spontaneous rosettes with sheep erythrocytes (E rosettes).

Autoimmune disease etiology--a perplexing paradox or a turning leaf?

Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, or scleroderma have been considered to represent disorders associated with reaction of the patient's own immune system against self-antigens or body systems. In many such disorders, tissues involved show lesions or morphology indicating destructive inflammatory or reactive features clearly produced by or associated with cell-mediated or antibody-driven reactions of the patient against his own tissues. After an exhaustive search which has stretched back in time for at least the last five decades, we seem to understand how the immune system works better than previously. However, despite the fact that we now understand molecular mechanisms of antibody selection and structure, how the cell-mediated and humoral antibody system is activated in terms of signal peptides and in the context of HLA molecules, we have not yet exactly identified inciting antigens which clearly cause these diseases. The focus recently has shifted towards being able to down-modulate potentially harmful parts of a self-directed inflammatory process by abrogating harmful messenger molecules participating in tissue injury. Following such a path, we may actually alleviate or cure these diseases before eventually identifying their original cause.

Studies of serum C-reactive protein in systemic lupus erythematosus.

OBJECTIVE: To examine the relationship of serum C-reactive protein (CRP) levels to other indicators of disease activity during the course of systemic lupus erythematosus (SLE). METHODS: In 124 patients serum CRP was measured retrospectively by ELISA and in some instances by radial immunodiffusion. Serum CRP levels were compared to laboratory, clinical, and radiographic assessments of disease activity. In many patients, serial CRP levels were measured over months or years to determine whether elevations of serum CRP reflected apparent changes in other disease activity variables. CRP was also measured in lyophilized aliquots of 24 h urine samples from SLE patients and controls with other renal disorders. Parallel determinations of interleukin 6 (IL-6) were made by ELISA in healthy controls and SLE patients. RESULTS: Of the 124 SLE patients studied, most showed elevations in serum CRP levels in the course of their disease. No inverse or direct correlation was noted between serum CRP and levels of nucleosome antigen or serum IgM or IgG anti-DNA antibody. In patients with renal involvement and proteinuria, CRP was often detected in 24-h urine samples. A strong correlation (p < 0.001) was noted between CRP and IL-6 levels in healthy subjects, but no correlation was recorded between serum CRP and IL-6 in SLE. CONCLUSION: Contrary to previous reports, most patients with SLE in our study showed elevations of serum CRP during the course of their illness, and extremely high serum CRP was recorded in some patients. CRP was also found in concentrated urine samples from patients with renal involvement and often paralleled elevated serum levels. In patients, no correlation was seen between CRP serum levels and serum IL-6, whereas a strong correlation between CRP level and IL-6 was recorded in healthy subjects.

Antibodies to microtubule-associated protein 2 in patients with neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: Microtubule-associated protein 2 (MAP-2), a cellular protein restricted to neurons, is important in the control of cytoskeletal integrity and other neuronal functions. We undertook this study to examine the presence of autoantibodies to MAP-2 in neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Sera from 100 patients with SLE, 74 patients with other neurologic disorders and injuries (including cerebrovascular accidents, brain trauma, brain tumors, and demyelinating disorders), and 60 normal controls were examined both by enzyme immunoassays and by Western immunoblotting for autoantibodies to MAP-2. Sera designated positive for antibodies to MAP-2 were required to be positive in both assays. RESULTS: Seventeen percent of SLE patients had autoantibodies to MAP-2, in contrast to 4% of neurologic injury/disease control patients (P = 0.028) and 1.7% of normal controls. In SLE, anti-MAP-2 positivity in both assays was associated with neuropsychiatric symptoms in 76.5% of patients, whereas the absence of anti-MAP-2 was associated with neuropsychiatric symptoms in 19.7% of patients (P = 0.0002). The neuropsychiatric symptoms in the former group included psychosis, seizure, neuropathy, and cerebritis. CONCLUSION: Autoantibodies to MAP-2, a neuron-restricted cytoskeletal protein, appear to be another immune marker for NPSLE.

Neuropsychiatric systemic lupus erythematosus presenting as amyotrophic lateral sclerosis.

A 61-year-old woman with a history of photosensitive dermatitis and recurrent mouth ulcers presented with progressive weakness typical of amyotrophic lateral sclerosis (ALS), and subsequently underwent extensive neurologic and rheumatologic testing. We investigated whether ALS-like motor neuron disease associated with a positive antinuclear antibody (ANA) is really ALS or rather neuropsychiatric systemic lupus erythematosus (NPSLE). On neurologic evaluation, she had prominent bulbar involvement with dysarthria and dysphagia associated with profound lingual fasciculations and a denervating pattern on electromyogram. MRI showed no evidence of cerebral ischemia. Laboratory studies revealed a positive ANA (1:2560 titer), positive antiphospholipid antibodies (GPL and MPL), circulating lupus anticoagulant, and depressed C3 and C4. Repeat MRI studies at 4 and 11 mo revealed an evolving infarct in the paramedian pons consistent with the presence of NPSLE. Therapy was initiated with corticosteroids and intravenous cyclophosphamide, and the neurologic condition did not improve, but also did not progress inexorably as would be expected with ALS. NPSLE, presumably through the mechanism of ischemic vasculopathy, may present as motor neuron disease clinically indistinguishable from ALS.