H. M. Moutsopoulos

Nephrocalcinosis in Sjögren's syndrome: a late sequela of renal tubular acidosis

Abstract. Sjögrens syndrome (SS) is an autoimmune exocrinopathy that develops into systemic autoimmune disease in 25% of patients, leading to general complications, one of which is kidney involvement. It presents mainly as interstitial nephritis, disclosed by hyposthenuria, distal renal tubular acidosis (RTA) and diabetes insipidus. We here describe five cases of SS with type‐1 RTA (hyperchloraemic metabolic acidosis with an anion gap and alkaline urine pH) who developed nephrolithiasis, nephrocalcinosis and renal insufficiency. Hypercalciuria due to acidosis was the main nephrocalcinosis‐prone factor in four patients; four subjects displayed diminished renal concentrating capacity, and two had hypokalaemia.

Cyclosporin-associated nephropathy in patients with autoimmune diseases

SummaryRenal biopsy specimens were evaluated from patients with different autoimmune diseases treated with cyclosporin (CyA). Ten biopsies were done before CyA, 10 biopsies after low-dose (<7.5 mg/kg/day, initial dose or mean daily dose within the first month, respectively), and 9 after high-dose (>7.5 mg/kg/day) treatment. Definite chronic CyA nephrotoxicity (cyclosporin-associated arteriolopathy and/or interstitial fibrosis striped form with tubular atrophy) was only present in the initial high-dose group. In this group a significant serum creatinine increase was noted and 8 of the 9 patients were hypertensive. No significant correlation was found between the severity of morphologic lesions and the mean daily dose during total treatment, cumulative dose, and duration of therapy. The morphologic changes in the low-dose group did not differ from the control biopsy specimens before CyA treatment. Based on these results, it can be concluded that major nephrotoxicity can be avoided by initial low CyA doses.

Xerotrachea and interstitial lung disease in primary Sjogren's syndrome

22 patients with primary Sjogrens syndrome were prospectively studied for respiratory system involvement with clinical, roentgenological and functional parameters. 12 patients (55%) had respiratory manifestations. In 10/12 (83%), respiratory symptoms occurred before or concomitantly with the classical symptoms of Sjogrens syndrome. There were two distinct forms of respiratory involvement: xerotrachea, manifested by dry cough without other symptoms and negative roentgenological and functional evaluation and diffuse interstitial lung disease manifested by dyspnea with or without dry cough with bibasilar rales, compatible chest roentgenogram, restrictive pattern in spirometry and/or hypoxemia. Xerotrachea was more common in patients with glandular form of Sjogrens syndrome (3/10) and diffuse interstitial lung disease in patients with extraglandular form (6/12). None of the 22 patients had pleurisy or other forms of respiratory involvement. Antibodies to Ro (SSA) and La (SSB) antigens were more common in patients with the extraglandular form of the syndrome but did not correlate with diffuse interstitial lung disease.

Labial minor salivary gland biopsy: a highly discriminatory diagnostic method between sarcoidosis and Sjögren's syndrome.

Sixty labial minor salivary gland biopsies (lip biopsies) from 32 patients with sarcoidosis and 28 patients with primary Sjögrens syndrome were evaluated retrospectively and blindly. Six biopsies revealed typical sarcoid granulomata. All six belonged to patients with previously diagnosed sarcoidosis. Twelve lip biopsies, all from sarcoidosis patients, were classified as presenting 1+ or less lymphoid infiltrates according to Tarpleys classification. The biopsies of the remaining 14 patients with sarcoidosis showed normal tissues. Finally, 28 biopsies were classified as having 2+ or 3+ lymphoid infiltrates and/or fibrosis. All belonged to patients with Sjögrens syndrome. Our results indicate that lip biopsy has a rather low diagnostic yield in sarcoidosis (19%) but, more importantly, it can discriminate very well between sarcoidosis and Sjögrens syndrome.

Immunologic and viral markers in the circulation of anti‐HIV negative heroin addicts

Abstract. To assess the degree of immune system activation associated with addiction or hepatotropic viruses infection, we examined 60 HIV‐negative heroin addicts for the presence of hepatitis B virus (HBV) infection markers, hepatitis C virus antibodies (anti‐HCV), various auto‐antibodies, and serum levels of soluble interleukin‐2 receptors (sIL‐2R). In addition, 28 anti‐HCV positive patients comprising the disease control group, were also examined. Our results demonstrated a high prevalence of anti‐HCV antibodies (61.7% and 90% with 1st and 2nd generation ELISA, respectively). Eighty‐seven percent (87Yi) of the addicts positive for anti‐HCV by the latter and 92.8% of the disease control patients, were also positive with 2nd generation recombinant immuno‐blot assay (RIBA‐II). In 88.9% of anti‐HCV positive addicts, antibody to C22–3 was the predominant (anti‐C33c in 81.5%). Antibodies to C33c and C22–3 polypeptides were also more frequent in disease control group (92.8% and 85.7%, respectively). Anti‐HCV antibodies were associated with increased transaminases (ALT or AST, P<0.05), as well as with longer duration of addiction (P<0.005). HBV infection markers (HBsAg, anti‐HBc only and anti‐HBs) were also present in the addicts (5%, 28.3% and 26.7%, respectively). Rheumatoid factors (RF) were detected in 36.7%, antinuclear antibodies (ANA) in 11.7%, antibodies (IgG and/or IgM) against cardiolipin (anti‐CL) and double stranded DNA (anti‐ds DNA) in 20% and 50%, respectively. RF, ANA, anti‐CL and anti‐dsDNA antibodies were also detected in the disease control group (32.10/, 89.3%, 28.5% and 28.5% respectively). Auto‐antibodies of at least one specificity, were found in 83.3% of addicts independently of anti‐HCV antibodies, HBV infection markers, increased ALT or AST levels, and the duration of addiction. They were, on the other hand, associated in addicts with antibodies to the C22–3 polypeptide of HCV (P = 0.0001) and with both of the predominant antibodies (anti‐C33c and anti‐C22–3) of the HCV (P<0.01 and P<0.05 respectively) in the disease control group. Thirty‐nine addicts (65%) and 50% of the disease control patients were found to have increased levels of sIL‐2R. In contrast to the disease control group, serum sIL‐2R levels of addicts were associated with RF (P<0.05), anti‐dsDNA (P< 0.0005) and total auto‐antibodies (P=0.0005), while there was a slight negative correlation with the duration of addiction (r= ‐0.26, P<0.05). However, sIL‐2R levels, were not associated with HBV and HCV infection markers in both groups. We conclude that intravenous heroin addiction appears to be associated with an increased prevalence of HCV and non‐organ specific auto‐antibodies. The latter may be driven by C22–3 and C33c polypeptides of HCV. Increased sIL‐2R levels attest to a cellular immune activation in addicts, which is slightly correlated with shorter duration of addiction, independently of HCV or HBV, but in association with auto‐antibodies production.

Renal tubular acidosis in primary Sjögren's syndrome

SummaryRenal tubular acidosis (RTA) is a frequent extraglandular manifestation of Sjögrens syndrome; however, no distinction on the incidence of this renal tubular defect between primary and secondary Sjögrens syndrome has been reported. This study was undertaken in order to define the frequency of RTA and the possible pathogenetic mechanisms in a group of 21 randomly selected primary Sjögrens syndrome patients. RTA was found in 7 (33%) patients. The incomplete type of the disorder was the most frequent. It seems that the etiology of RTA is multifactorial. Renal excretion of monoclonal proteins and the immunologically-induced interstitial inflammation are the main possible factors of this renal tubular defect.

Patients with anticardiolipin antibodies with and without antiphospholipid syndrome: their clinical features and β2-glycoprotein-l plasma levels

Abstract. The clinical and serological features of 38 aCL‐positive patients were compared to those of 45 aCL‐negative patients. A significantly higher incidence of thrombophlebitis and livedo reticularis was found in aCL‐positive patients. There were 13 aCL positive patients with thrombophlebitis and/or arterial thromboses and these 13 patients were designated as having the antiphospholipid syndrome (APS) while the remaining 70 patients were diagnosed as having Systemic Lupus Erythematosus (SLE). APS patients also had a high incidence of arterial occlusions, recurrent abortions and strokes compared to SLE patients. Patients with high levels of IgG‐aCL were more likely to have APS, while patients with low levels of IgG‐aCL or IgM‐aCL only were more likely to have SLE without the clinical features of APS. Since aCL antibodies have recently been shown to interact with a phospholipid‐binding plasma proteinβ2‐glycoprotein‐I (β2‐GPI), we measured the β2‐GPI levels in these patients and found thatβ2‐GPI levels are significantly higher in APS compared to SLE patients negative for aCL antibodies. Sinceβ2‐GPI is known to exert multiple effects on coagulation processes the interaction of aCL antibodies with this glycoprotein may play a pathogenic role in APS.

Anti-Ro (SSA)/La (SSB) antibodies and Sjögren's syndrome

SummaryAntibodies to Ro (SSA) and La (SSB) cellular ribonucleoprotein complexes are found in the circulation of patients with Sjögrens syndrome (SS), mainly in those with the primary form of the syndrome. Their presence is associated with long disease duration, earlier disease onset, parotid gland enlargement, systemic manifestations and also with hypergammaglobulinemia, rheumatoid factors and monoclonal type II cryoglobulins. While anti-Ro (SSA) antibodies are not specific for SS, anti-La (SSB) antibodies seem to be specific. Studies of HLA class II molecules in Ss patients with and without these antibodies have shown that their production is under genetic control. Finally, there is no conclusive evidence relating pathogenetically these autoantibodies to tissue destruction in SS.

Lack of HLA-antigen association in Greek rheumatoid arthritis patients

SummaryOne hundred and eighteen unrelated Greek patients with classic rheumatoid arthritis (RA) were tissue-type for HLA-A, -B, -DR antigens and the frequency was compared to that of healthy controls. Greek RA patients regardless of sex, anatomical severity, seropositivity and age at disease onset are not associated with any of the HLA alloantigens tested. Only an increased prevalence, not statistically significant, was observed of the HLA-DF-5 antigen in the Ro(SSA) positive RA group.

Methotrexate therapy in rheumatoid arthritis. A two year prospective follow-up.

SummaryOne hundred and thirty seven rheumatoid arthritis (RA) patients refractory to D-penicillamine and some of them (15%) refractory to other slow active drugs were treated with oral methotrexate (MTX) (10–15mg weekly). After 12–24 months of treatment, 94 and 74 patients respectively showed a significant improvement as judged by duration of morning stiffness (p<0.0001), grip strength (p<0.0001), degree of joint swelling (p<0.01) and tenderness (p<0.0001) compared to pre-treatment values. This clinical improvement was also associated with a decrease of erythrocyte sedimentation rate (p<0.0001), decrease of C-reactive protein (p<0.0001) and with improvement of anaemia (p<0.05). No changes were seen in rheumatoid factor titres. Seventy-four of the patients were followed for up to 24 months. Thirty-one of them (23%) had complete remission and 43 (31%) had an excellent response. Adverse drug reaction during MTX therapy included: elevated liver enzymes in 34 patients, mucosal ulcers in 21, nausea and vomiting in 8, diarrhoea in 4, leukopenia in 2, interstitial pneumonitis in one, intestinal bleeding in one and finally septic arthritis in another patient. The majority of these side effects were resolved without sequelae. However, 15 patients (11%) with adverse drug reactions had to discontinue the treatment. Forty-one of our patients who received a cumulative mean dose of MTX of 1550.5±235.5 mg underwent a percutaneous liver biopsy. Ten patients had normal tissue, 12 had minimal changes, 13 nonspecific changes and 6 patients had mild fibrosis. We conclude that MTX therapy in refractory RA patients appears to be effective, but requires close monitoring for toxicity. Hepatotoxicity with fibrosis and cirrhosis due to long term MTX therapy may be relatively uncommon in RA patients.