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Lung involvement is rarely observed in the DRESS syndrome (Drug rash with eosinophilia and systemic symptoms). We report here a severe minocycline induced hypersensitivity syndrome with initial respiratory distress.A 19 year old man was admitted to the intensive care unit for acute respiratory distress with fever (400C), lymph node enlargement, hepatomegaly, splenomegaly and eosinophilia (1640/mm3). Bilateral alveolar opacities were observed on the chest x-ray. Sedation and mechanical ventilation rapidly became necessary because of severe hypoxaemia (47 mm Hg) and the sudden onset of severe aggressive behaviour. The diagnosis of DRESS was immediately suspected as the patient had been treated for acne with minocycline for 28 days, and IV corticosteroids (2 mmg/kg/day) were initiated. Skin lesions were delayed and appeared 3 days later. The outcome was uncertain for the following 6 weeks with serious disturbance of hepatic and renal function. Serology for human herpes virus (HHV6) was initially negative but became positive. One year later, after progressive withdrawal of corticosteroid therapy, the patient had made a complete recovery with no sequelae.The DRESS syndrome can cause considerable morbidity with multiple, severe visceral functional disturbances. Respiratory physicians should be aware of this syndrome as lung involvement can be serious and may precede cutaneous symptoms.

It is not unusual for respiratory specialists to be called to deal with respiratory problems in pregnancy. However, some conditions, such as tocolysis-induced pulmonary edema, although common, are largely unknown to our specialty. We report on the cases of three pregnant women, who developed pulmonary edema in the context of tocolysis with the intra-venous infusion of B-agonists. In all three patients, tocolysis was required because contraction developed well before term. Triple pregnancy was present in one patient. In another patient, mechanical ventilation was required. The outcome was good with full recovery in all three cases.

Twenty one cases of the association systemic scleroderma and cancer are reported. Neoplasic localisations were the following: pulmonary five cases; breast two cases; esophageal cancer one case; stomach one case; colon one case; uterus four cases; ovarian cancer one case; prostatic cancer one case; renal cancer one case; malignant hemopathies six cases. In the literature, more than three hundred cases of such an association have been reported since 1886, essentially lung cancers (more than 100). Recent epidemiological studies allow to conclude to a higher frequency of lung and breast cancers. We suggest that systemic scleroderma patients should be examined attentively and carefully for these risks.

We identified eight patients (six women and two men) who had pulmonary infiltrates during treatment with minocycline hydrochloride between 1989 and 1992 in French referral centers for drug-induced pulmonary diseases. Clinical files, chest roentgenograms, computed tomographic scans, pulmonary function, and bronchoalveolar lavage data were reviewed. Minocycline treatment was given for acne (n = 4), genital infection (n = 3), and Lyme disease (n = 1). The duration of treatment averaged 13 +/- 5 days (mean +/- SE); the total dose, 2060 +/- 540 mg. Patients presented with dyspnea (n = 8), fever (n = 7), dry cough (n = 5), hemoptysis (n = 1), chest pain (n = 2), fatigue (n = 3), and rash (n = 3). Chest roentgenograms showed bilateral infiltrates in all cases. Pulmonary function was measured in five patients; four had airflow obstruction and two had mild restriction. Blood gas tests demonstrated hypoxemia in seven patients (58 +/- 3 mmHg). Seven patients had blood eosinophilia (1.76 +/- 0.2 x 10(9)/L). Bronchoalveolar lavage (performed in seven patients) showed an increased proportion of eosinophils (0.30 +/- 0.07). The Cd4+/CD8+ ratio was determined in four cases and was low in three. Transbronchial lung biopsy, performed in two patients, showed interstitial pneumonitis in both patients, with marked infiltration by eosinophils in one patient. The outcome was favorable in all patients. Because of severe symptoms, steroid therapy was required in three patients. Rechallenge was not attempted. We conclude that minocycline can induce the syndrome of pulmonary infiltrates and eosinophilia, that presenting symptoms may be severe and may culminate in transient respiratory failure, and that the disease has a favorable prognosis.

Respiratory involvement in patients with inflammatory bowel disease (IBD) has been reported mainly since 1976. This form of involvement should clearly be separated from interstitial lung disease due to sulfasalazine or mesalamine, although the distinction may be difficult in some cases. We report the data of an ongoing Registry containing 33 cases (23 cases receiving no drug therapy) with ulcerative colitis or, less often, Crohn's disease, who developed varied bronchopulmonary problems. In several cases, the exact diagnosis and the relation of the bronchopulmonary disease to IBD had not been established for many years, thus delaying effective treatment with steroids. In most cases (28/33), respiratory involvement followed the onset of IBD (8 of these 28 cases were postcolectomy), and in the remainder, respiratory manifestations predated the IBD. Patterns of involvement included: 1) Airway inflammation, in the form of subglottic stenosis, chronic bronchitis, severe chronic bronchial suppuration, bronchiectasis, and chronic bronchiolitis. In cases with large airway involvement, endoscopy showed exuberant inflammatory tissue in the airways and narrowing of tracheal and/or bronchial lumen. Histologically, airways were heavily infiltrated by a dense aggregate of inflammatory cells, and there were mucosal ulcerations. 2) Varied patterns of interstitial lung disease, mainly bronchiolitis obliterans with organizing pneumonia, and pulmonary infiltrates and eosinophilia. (3) Miscellaneous other forms of involvement including striking neutrophilic necrotic parenchymal nodules (corresponding histologically to sterile aggregates of neutrophils), and serositis. Steroids were very effective in the majority of cases. Inhaled steroids were of durable benefit in patients with chronic bronchitis, but less often so in those with chronic bronchial suppuration, bronchiectasis, or chronic bronchiolitis. Steroids administered orally led to marked improvement in patients with interstitial lung disease and necrotic nodules, but lacked effectiveness in several patients with severe airway inflammation or chronic bronchiolitis. Intravenous steroids were required in the initial management of life-threatening complications such as asphyxiating subglottic stenosis or extensive interstitial lung disease. Bronchial lavages with methylprednisolone were effective in some patients with severe airway inflammation. Patients with IBD can develop varied inflammatory complications in the lung, and a sizable fraction of these complications is steroid-sensitive.

We describe avascular necrosis at multiple sites in 2 young adults. This is a condition rarely seen except in hypercortisonism or hemoglobinopathies. In one case, it occurred in the first trimester of pregnancy. No obvious cause of osteonecrosis could be found but both patients were infected by the HIV. The role of the latter in the bone necrosis is questionable.

Pyrithioxine, a chemical compound with several points in common with penicillinamine, was used for six months as the basic treatment in a series of 60 cases of rheumatoid arthritis, in a dose of 600 mg per day. The results were favourable in 60 per cent of cases, with a marked fall in articular index, a return to normal of sedimentation rate and, less commonly, negativisation of the Rose-Waaler reaction. Side effects were essentially cutaneo-mucosal (pruitus, rash) and necessitated the interruption of treatment in 16.5 per cent of cases. No complications were seen. Compared with penicillinamine, pyrithioxine appears to be less effective but better tolerated. The place of this new basic drug in the basic treatment of rheumatoid arthritis remains to be precisely determined.

A case of two families with a total of 5 cases of generalized cortical hyperostosis of the cortex of the long bones is clinically latent. It is not accompanied by any osseous fragility and is usually discovered by chance. Mandibular hypertrophy can occur but is not constant. It must be differentiated from the recessive form described by Van Buchen, which is more severe and involves extensive and progressive osteocondensation which can lead to paralysis of the cranial nerves. The small number of cases published (23) leads one to suppose that its diagnosis is frequently missed, undoubtedly because it is mixed up with a minor form of osteopetrosis.

Three cases of benign connective tissue tumors (intracranial frontal hemangiopericytoma, rectosigmoid hemangioma, intraspinal neurinoma) associated with hypophosphoremic osteomalacia and reduction in plasma 1-25 (OH)2D levels are described. Rapid reversal of biological anomalies and subsequent recovery from clinical manifestations were observed after tumor ablation. Twenty-two identical cases have been reported in the published literature. The sharp- fall in 1-25 (OH)2D levels without secondary hypocalcemia or hyperparathyroidism suggests that intestinal absorption of calcium is not entirely dependent on this metabolite. Increased phosphoremia without a parallel rise in 1-25 (OH)2D levels was noted in one case. The possibility of an existing connective tissue tumor should be explored in all cases of hypophosphoremic osteomalacia.

We describe 3 cases of upper airway obstruction in which no organic cause could be identified. All 3 patients presented with severe dyspnea and stridor. Direct laryngoscopy and bronchoscopy failed to demonstrate any lesion. Flow-volume loops showed a pattern of severe variable extrathoracic airway obstruction with a decreased peak inspiratory flow and an increased ratio of the forced expiratory flow at 50% vital capacity to the forced inspiratory flow at the same lung volume. Plethysmographically measured airway resistance was normal in the 2 patients for whom it was obtained. We believe a functional etiology should be added to the possible causes of acute upper airway obstruction. This entity can readily be identified by the marked discrepancy between inspiratory flow limitation and airway resistance.

Pyrithioxine has certain chemical resemblances to penicillamine and is used as original treatment in a series of 72 cases of rheumatoid arthritis over a period of six months in a dose of 600 mgs daily. Results were favourable in 63% of cases with important lowering of the articular index, return to normal of the sedimentation rate and less frequently a reversal of the Waaler-Rose reaction. Secondary complications were essentially muco-cutaneous, sometimes gastric and necessitated stopping treatment in 15% of cases. No other serious side effect has been observed. When compared with penicillamine pyrithioxine would appear less efficacious but better tolerated. The usefulness of this new medicament in the treatment of rheumatoid arthritis needs to be further explored.

Whipple's disease is a systemic illness whose pathogenesis, which is still poorly understood, implies an infectious agent accessible to antibiotic therapy. The authors report a case which is made unusual by the manifold systemic manifestations, important eosinophilia and destructive nature of the joint lesions of the hips. The physiopathological mechanisms of ocular and cutaneous manifestations are considered. A dramatic improvement is obtained with tetracyclin.

49 unrelated subjects suffering from systemic scleroderma were typed for 28 HL-A antigens, without any particular significant association of an antigen with the disease or one of its manifestations being noted. In addition, 13 patients from the same family were genotyped for HL-A. Transmission of the disease through 4 generations does not seem to be linked to a particular haplotype and no pair of sibling HL-A identical patients were seen in the same generation. By contrast, two pairs of sibling patients were HL-A different. Nevertheless, other cases, and in particular familial, will be necessary before an association between the genes of susceptibility to S.S. and a gene in the chromosomal HL-A region may be definitely eliminated.

We present five cases of severe osteoporosis accompanied by a skin and/or bone mastocytosis. The rarity of mastocytosis demonstrates that these cases are not the result of simple coincidence, especially since none of them involves other general of phospho-calcium anomalies that could explain the demineralization. The latter is accompanied by a high level of histaminemia or histaminuria, a non-specific anomaly. Mastocyte osteoporosis involves a great many unknown factors on the physiopathological level, but in practice it is necessary to look for a mastocytosis when confronted with a severe osteoporosis that appears to be primary. Cytostatic treatment (chlorambucil, cyclophosphamide) seems capable of improving the evolution of the bone disease.

Two new SH-CH3-containing drugs have been studied as penicillamine-like agents. Pyrithioxine--retrospectively compared to a D-penicillamine series--was associated with fewer side effect-related withdrawals (14 vs 39) but with more non-responses and withdrawals for relapse. A review of the literature shows that thiopronine and D-penicillamine have a similar "score" of side effects and good responses. More extensively-controlled trials are needed for a better assessment of these new drugs.

A 39 year old female with severe respiratory insufficiency by bronchiectasis is treated by assisted ventilation at home. Indication is discussed.

Quantitative analysis of urinary cyclic AMP in phospho-calcic pathology. The authors describe a method measuring amounts of cyclic AMP. Normal daily elimination in urine was measured in a group of normal subjects. Elimination was found to be raised in two-thirds of the patients with primary hyperparathryroidism, normal in those with idiopathic hypercalcaemia and neoplastic hypercalcaemia, and subnormal in patients with hypoparathyroidism. The urinary excretion of cyclic AMP after perfusion of parathyroid hormone was very low in cases of pseudo-hypoparathyroidism compared with that in surgical hypoparathroid controls. The results are compared with data from the literature. The theoretical and diagnostic value of these quantitative analyses is discussed.

The authors present their own series of 70 rheumatoidpolyarthritis cases treated with pyrithioxine during one year or more except in the case of failure or intolerance. The following results were observed after one year: 54 percent showed positive results, 34 percent showed no results or dubious ones, and there was 13 percent of discontinuance because of intolerance. Modifications of the posology and methods of administering are proposed, and the role of pyrithioxine, as a basic treatment for rheumatoid polyarthritis, is discussed.

Thirty-one unrelated patients, 15-52 years old, were typed by microlymphocytotoxicity for 27 alleles of the HLA system. In addition, 12 families including 1 or more patient were also analysed. This criteria for diagnosis were those of Sohar et all. (Am. Intern. Med., 1967, 43, 227-253). All patients were of Israelite-Sephardin origin except two (Armenian and French); they were from North-Africa (Tunisia, Morocco and Algeria) and Israël. The results were compared to the antigen frequencies of 3 reference normal populations. The frequencies of the studied alleles do not differ from those of controls, except for HL-A28 and B14 slightly increased when compared to the normal frequencies. The study of 7 families with at least two sibs suffering from FMF shows a random distribution of the genotypes : 2 HLA identical, 6 different and 10 haploidentical diseased sibs. This distribution differs significantly (p less than 0.01) from that expected in the case of a recessive inheritance. These data do not support the hypothesis of a linkage between genes controlling FMF and HLA genes.

One hundred ninety-five patients suffering from active rheumatoid arthritis were included in a two-week double blind multicentric study, whose purpose was to compare the efficacy and tolerance of a daily dose of 600 mg of pirprofen to that of 1200 mg and the placebo. The results show that there is a dose-effect relationship of definite clinical interest. Thus, the investigators judged the clinical results satisfactory in 60% of the patients in the 1200 mg group (400 mg t.i.d.) 44% of those in the 600 mg group and 36% of those on placebo. The difference is statistically significant (p less than 0.05). Side effects, primarily digestive, were noted in 34% of patients receiving 1200 mg/day, 15% of 600 mg/day and 32% placebo. 2 patients in the 1200 mg group interrupted their treatment for gastralgia and 1 patient on placebo for palpitations.

This study involved three adult men and six elderly individuals (3 men and 3 women). Adult subjects served as the control group. All subjects were given one dose of 10 microCi of tritiated vitamin D3 (approximately 15 IU) per os. Blood samples were taken 5 min., 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h and 192 h after administration of vitamin D3. The concentrations of tritiated vitamin D3 and 25-hydroxyvitamin D3, its principal metabolite, were measured in each sample after extraction and purification by high performance liquid chromatography (HPLC). In addition, two adult subjects and three elderly women subjects were given an identical dose of tritiated vitamin D3 approximately 10 days following the end of the initial experience. Blood samples were collected at the times indicated above and analyzed in identical fashion. The percentage of intestinal absorption of vitamin D3 and the amount of vitamin D3 metabolized to 25-hydroxyvitamin D3 were calculated as were the time constants for vitamin D3 and 25-hydroxyvitamin D3 disappearance curves. Review of these parameters confirmed that significant individual variations exist for intestinal absorption of vitamin D3. Study results did not furnish any evidence of a decrease in 25-hydroxylation of vitamin D3, nor any increase in the rate of disappearance of vitamin D3 or 25-hydroxyvitamin D3 which might explain the very low levels of 25-hydroxyvitamin D3, often found in aged persons.

The authors present a short series (6 cases) of serum positive rheumatoid arthritis, treated by I.M. injections (5 cases) or intra-articular injections (one case) of dismutase superoxide of bovine origin. The treatment was stopped in one case for local intolerance. Four cases treated for four months by the intramuscular route, were uninfluenced by the treatment, nor was the patient treated by the intra-articular route. The laboratory parameters (E.S.E., Rose Waaler reaction) were not modified. On the other hand, the lymphocyte fragility in culture was improved. The good tolerance of this compound in the laboratory will permit further trials in higher dosage.

The authors present a series of 120 cases of sero-positive rheumatoid arthritis followed for ten years and treated with D-penicillamine, gold salts and pyrithioxine used either alone or sequentially after stopping one of these treatments because of failure, intolerance or escape. This series can be broken down as follows: 13% of patients are under treatment after ten years, 27% had a favourable result with one of the three treatments for five to ten years, 59% had a poor result (less than 5 years) or no effect. However, it appeared that a failure or an escape from one of these products did not signify a failure with another product and side effects did not necessarily recur with a change of treatment.

Two cases of inflammatory joint disease during attacks of aseptic palmo-plantar pustulosis are reported. Both patients had vertebral involvement: disco-vertebral erosions at several levels in one case and spondylitis and intersomatic ossification in the other. One patient also had sacroiliitis and involvement of the anterior thoracic skeleton (costoclavicular joints, costal cartilages ans xiphoid) confirmed by bone scintigraphy. The relation between this cutaneous-articular syndrome and other inflammatory joint diseases, especially ankylosing spondylitis and psoriatic arthropathy are discussed. The very unusual involvement of the anterior thoracic skeleton, the coexistence of aseptic palmo-plantar pustulosis and absence of antigens HLA B27, B13 and B17 suggest a similarity to the pustular osteoarthritis recently described by Japanese workers who grouped this condition with other spondylarthropathies.

Osteoporosis is the result of the progressive loss of bone substance which occurs during a lifetime. Its histomorphological characteristics have been well-defined and it appears to be a single entity more particularly related to the general problem of cellular senescence. The rate at which bone is lost can be influenced by many events or general factors, known or unknown, which are capable of accelerating or slowing down its progression. The period when the fracture threshold is passed appears to depend on a bone mass which is weak at the end of the growth period, followed by genetic, mechanical--related more specifically to insufficient muscular activity--, hormonal-hypo-oestrogenemia-factors, and pathological episodes of more rapid demineralization (immobilization, corticotherapy) which become more irreversible with advancing age.The absolute osseous volume regularly diminishes throughout a lifetime; it is one of the phenomena of cellular senescence, due to the lack of necessary elements (calcium, proteins, phosphorus), and to decreasing osteoblastic activity. There are factors which accelerate this process of bone consumption; they can be costitutional factors, such as sex, race, and country of origin; or mechanical factors, such as forced immobilization, or insufficient muscular activity. Hormonal factors causing or accelerating osteoporosis are corticotherapy, hyperthyroidism, and lack of estrogens. Nutritional factors include a diet poor in calcium and in vitamin D.

The effectiveness of Bi-Profenid tablets and Profenid capsules was studied comparatively in patients with inflammatory joint disease. 43 patients with rheumatoid arthritis or various chronic inflammatory joint diseases were given 300 mg of Bi-Profenid in 2 daily oral doses and 300 mg of Profenid in 3 daily oral doses, for two consecutive 7 day periods. This double blind cross-over study was carried out in two rheumatology centers. Effectiveness of the two forms of ketoprofen on morning stiffness and pain scale was found to be comparable. However, patients more often preferred Bi-Profenid (15 cases) to Profenid (10 cases); 12 patients reported no difference. Tolerance was excellent in 92.7% of cases under Profenid capsules and in 94.8% of cases under Bi-Profenid tablets.

Comparative study of the numbers of T and B lymphocytes in cases of rheumatoid polyarthritis treated and untreated with D-penicillamine shows that in the untreated subjects the distribution of these two types of lymphocytes is comparable with that in normal subjects and that D-penicillamine does not alter this distribution. This purely quantitative investigation does not rule out the possibility of functional modifications in the cells studied.

After reviewing the history of the discovery of the action of D-penicillamine in rheumatoid arthritis, the authors define the practical modalities for the management of treatment based on their own experience and on the data from the literature. The therapeutic score remains relatively low because of the frequency of side effects and therapeutic escapes, even when an encouraging result has been obtained during the first years of treatment.

The authors undertake a general review of the association between hypophosphoraemia and connective tissue tumour, based upon three personal cases and 27 cases of benign connective tissue tumours, as well as cases of hypophosphoraemia related to malignant tumours or to diffuse dysplasia of connective tissue origin, collected from the literature. This syndrome is distinguished from hypophosphoraemia induced by other tumours (myeloma, carcinoma of the prostate) which are based upon different mechanisms. Hypophosphoraemia, associated with a fall in plasma levels of 1-25 (OH)2 D3 by inhibition of renal 1 alpha hydroxylase, suggests the existence of a complex tubular deficit. Removal of the tumour, most often vascular and intra- or para-osseous, results in rapid normalisation of laboratory then radiological and clinical abnormalities. The physiopathology of the syndrome remains very mysterious. It may be likened to certain tubulotoxic syndromes due to cadmium and in particular to maleic acid. However no precise data yet exists regarding any possible abnormal tumour secretion. In practice, any case of hypophosphoraemic osteomalacia requires investigation to locate a possible tumour of connective tissue, and this all the more so when it is accompanied by very low plasma levels of 1-25(OH)2 D2.

Five patients with typical seropositive rheumatoid arthritis were treated by plasma exchange. All patients had severe affections resistant to conventional treatment, while in four cases the disease involved extra-articular localizations: rheumatoid nodules (3 cases), polyneuritis (1 case), skin necrosis (1 case). Each patient received between 5 and 10 plasma exchanges over a period of 3 to 4 weeks. No major complications were observed. Immediate results were very good in all cases, as shown by absence of clinical expression of the arthritis, marked regression in extra-articular symptoms, and reduction in erythrocyte sedimentation rate without parallel alterations in rheumatoid factor levels. Improvement lasted for only a few weeks in 3 patients, in one case preceded by an acutely painful episode. In the remaining 2 cases, with associated vasculitis, improvement has been sustained for a period that now exceeds one year. Results are compared with those reported in the published literature, and the mode of action and indications for plasma exchange in rheumatoid arthritis discussed.