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A 49-year old man suffered a superficial injury on the dorsum of the right hand. Subsequently, a wound developed which healed slowly despite several courses of oral antibiotics. Gradually, nodular lesions developed on the hand. A biopsy of the nodules showed granulomatous inflammation which was considered to be consistent with rheumatoid nodules. Local injections with corticosteroids were administered with only temporary relief. Eigtheen months after the original injury a biopsy was performed and sent for bacterial culture which grew Mycobacterium marinum. The patient received prolonged antimycobacterial treatment. Nevertheless, osteomyelitis eventually developed and a second course of drug therapy, as well as a surgical operation was required before the infection was eventually cured.

Objective: A functional deficiency of complement has been implicated but not conclusively demonstrated in the pathogenesis of systemic lupus erythematosus (SLE). To test this, we studied several aspects of complement in 44 patients with SLE, 46 patients with rheumatoid arthritis and 102 blood donors., Methods: Prevention of immune precipitation (PIP) was measured by an enzyme immunoassay, levels of C1q, C4 and C3 by rocket immunoelectrophoresis, C4A, C4B and C3d by enzyme-linked immunosorbent assay (ELISA), complement haemolysis (CH50) by standard methods and C4 allotypes by high-voltage agarose electrophoresis and sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE)., Results: PIP was significantly reduced in SLE (P<0.001); the defect was revealed by a sensitive assay measuring this function of complement but not by the other tests employed. The patients were clinically well at the time of study, and levels of C3d, which have been shown to correlate with disease activity, were normal. The defect was more common in patients with early disease (P = 0.009), supporting a role in aetiology or early pathophysiology. PIP was positively correlated with levels of C4 (P = 3 x 10(-5)) and in particular the C4A isotype (P = 9 x 10(-10)) whereas C4B was redundant., Conclusions: Our results reveal a defect in prevention of immune precipitation in SLE that is apparent at an early stage in the disease and correlates with low levels of C4A. These results indicate that subtle deficiencies of complement may predispose to SLE.

Objective: To study the frequency of a C4A gene deletions as the genetic basis of C4A protein deficiency (C4AQ0) and its associated haplotypes in Icelandic families with systemic lupus erythematosus (SLE)., Methods: Nine multiplex SLE families were genotyped for C4A gene deletions using a long-range polymerase chain reaction (LR-PCR) method, and major histocompatibility complex (MHC) haplotypes were defined., Results: Of the SLE patients, first-degree and second-degree relatives, 53.8%, 47.9%, and 28.6% had C4AQ0, respectively. A C4A gene deletion was found to be the genetic basis for C4AQ0 in 64.3% of SLE patients, 60.0% of first-degree and 50.0% of second-degree relatives. All individuals carrying haplotype B8-C4AQ0-C4B1-DR3 had a deletion, and the deletion was also found on haplotypes B8-C4AQ0-C4B1-DR7 and B7-C4AQ0-C4B1-DR3., Conclusion: The study shows that a C4A gene deletion is the most common genetic basis for C4AQ0. It accounts for two-thirds of C4AQ0 and is found on different MHC haplotypes. One-third of C4AQ0 is due to other as yet undefined genetic changes. The results demonstrate a heterogeneous genetic background for C4AQ0, giving further support for the hypothesis that C4AQ0 may be an independent risk factor for SLE.

In the present literature there is still controversy as to whether patients with systemic lupus erythematosus (SLE) are at increased risk of developing malignant diseases. In recent years a number of epidemiological studies have been conducted and some have suggested an association between SLE and malignant diseases while other studies have not. The objective of this study was to investigate this relationship in an unselected cohort of Icelandic patients with SLE. All patients diagnosed with SLE registered in the Icelandic SLE database were compared to the Icelandic cancer registry. For completeness, hospital charts and outpatient notes were also reviewed. The study period was from 1957 to the end of 2001. The O/E (observed/expected ratio), CI and P-value were calculated for total number of malignancies as well as individual malignancy types. Of 238 patients diagnosed with SLE (213 women and 25 men) 39 malignancies were diagnosed in 36 patients; 32 women and four men. Of the 36 patients, 27 were diagnosed subsequently with SLE and malignant disease. The mean age at diagnosis of SLE was 43.2 years (range 10-81) and at time of diagnosis of malignancy 62.7 years (range 43-86). The O/R for the whole study population was 1.38 (CI 0.89-1.87, P = 0.063), 1.45 for the women (CI 0.91-1.99, P = 0.051) and 1.03 for the men (CI 0.22-2.66, P = 0.560). The O/R for the most frequent malignancies diagnosed subsequently to SLE was 6.43 for squamous cell skin cancer (CI 1.31-18.5, P = 0.012), 5.48 for lymphoma (CI 0.64-19.6, P = 0.052), 2.46 for uterine cancer (CI 0.29-8.78, P = 0.196), 2.0 for ovarian cancer (CI 0.23-7.14, P = 0.264), 1.72 for lung cancer (CI 0.36-4.95, P = 0.254) and 1.6 for breast cancer (CI 0.65-3.23, P = 0.154). The total number of patient-years at risk was 2774 years. The results from this study on an unselected cohort of Icelandic SLE patients do not suggest an overall association between SLE and malignancy. Squamous cell skin cancer was the only individual cancer type that was statistically increased in the population and the numbers for lymphoma were borderline statistically significant.

Systemic lupus erythematosus (SLE, OMIM 152700) is a complex autoimmune disease that affects 0.05% of the Western population, predominantly women. A number of susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes and mutations is yet to be identified. We previously reported a susceptibility locus (SLEB2) for Nordic multi-case families. Within this locus, the programmed cell death 1 gene (PDCD1, also called PD-1) was considered the strongest candidate for association with the disease. Here, we analyzed 2,510 individuals, including members of five independent sets of families as well as unrelated individuals affected with SLE, for single-nucleotide polymorphisms (SNPs) that we identified in PDCD1. We show that one intronic SNP in PDCD1 is associated with development of SLE in Europeans (found in 12% of affected individuals versus 5% of controls; P = 0.00001, r.r. (relative risk) = 2.6) and Mexicans (found in 7% of affected individuals versus 2% of controls; P = 0.0009, r.r. = 3.5). The associated allele of this SNP alters a binding site for the runt-related transcription factor 1 (RUNX1, also called AML1) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.

Objective: Studies of an Icelandic cohort showed that susceptibility to systemic lupus erythematosus (SLE) in individuals with C4A deficiency was increased only in the presence of increased concentrations of immune complexes. We investigated the interaction of C4A deficiency with elevated concentrations of immune complexes in healthy individuals; i.e., how different levels of C4A affected the activation of C4 and C3 and subsequent binding of increased immune complex load to human red blood cells (RBC)., Methods: Forty-five healthy individuals having different levels of C4A were studied, 8 with homozygous C4AQ0, 12 with heterozygous C4A deficiency, and 25 with normal C4A. For comparison to the complement status present after prolonged disease activity, 5 patients with SLE homozygous for C4AQ0 were also studied., Results: The results showed that intact immune complex-RBC binding is dependent on the levels of immune complex-bound C3 fragments, which correlate to the levels of IC-bound C4Ad (R = 0.677, p = 0.02), but not on levels of IC-bound total C4d (R = 0.451, p = 0.16). Immune complex binding to RBC was also evaluated in increasing immune complex load. C4A deficient sera had less ability to bind the increased immune complex load to RBC than sera with normal C4A. These results are consistent with the presence of increased amounts of poorly opsonized immune complexes in C4A deficiency, leading to increased precipitation in tissues and initiation of a self-perpetuating cycle., Conclusion: Susceptibility to SLE is increased in individuals with C4A deficiency as C3 opsonization of immune complexes becomes insufficient at elevated immune complex concentrations.

The objective of this study was to evaluate apoptosis and production of IL-10 in SLE patients, their spouses and first-degree relatives in Icelandic SLE multicase families. Previously, increased IL-10 production has been found in all three groups. As IL-10 has been found to induce apoptosis in SLE, the percentage of lymphocytes undergoing apoptosis was evaluated, as well as the possible correlation between apoptosis and IL-10 production. Apoptosis and IL-10 production were studied in SLE patients (n = 12) from SLE multicase families and their spouses (n = 12) and a matched control group of healthy individuals (n = 10). The proportion of T and B lymphocytes undergoing apoptosis at 0, 24, 48 and 72 h was detected by flow cytometry using Annexin V and PI staining and the rate of apoptosis was calculated. IL-10 production was studied simultaneously by ELISpot analysis of freshly isolated peripheral blood mononuclear cells. In addition, T lymphocyte apoptosis at t = 0 was investigated in a group of non-household first-degree relatives (n = 10) and controls (n = 10). Antinuclear and antilymphocyte antibodies were analysed in all the groups. The SLE patients as a group had a significantly increased percentage of T lymphocytes in apoptosis at 0 and 48 h and a significantly higher number of IL-10 producing cells as compared with the healthy controls (P = 0.03, 0.02 and 0.03, respectively). The spouses also had significantly increased percentage of T lymphocytes in apoptosis (t = 0) and a significantly higher number of IL-10-producing cells when compared with healthy controls (P = 0.01 and 0.02, respectively). There were no significant differences between the patients and their spouses. For apoptosis of B lymphocytes no difference was found between the groups. The SLE patients as a group had the highest rate of apoptosis. No correlation between the degree and rate of apoptosis and the number of IL-10-producing cells was detected. The first-degree relatives did not have increased percentage of T lymphocytes undergoing apoptosis at t = 0 compared with healthy controls. The SLE patients had higher titres of ANA compared with the other groups. No correlation was detected between the ANA titre and the percentage of lymphocytes undergoing apoptosis. There was no correlation between disease activity as measured by SLEDAI and apoptosis. In conclusion, our results suggest that environmental factors common to both SLE patients and their spouses are associated both with the increased apoptosis and increased spontaneous production of IL-10, thus providing support for the notion that both environmental and genetic factors influencing apoptosis are of importance for the development of SLE.

Objective: Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis. Although there is a large body of evidence suggesting that RA is immune mediated, the etiology remains unresolved. Twin studies have shown disease concordance rates of approximately 15% in monozygotic twins and 4% in dizygotic twins, while the estimated risk ratio for siblings of RA patients ranges from 5 to 8. Our goal was to use genealogic data from Iceland to further investigate the genetic component of RA., Methods: Data were obtained from a population-based, computerized genealogy database that was developed to examine multigenerational relationships among individuals in the relatively homogeneous population of Iceland. Using an algorithm, the minimum founder test, we calculated the least number of founders required to account for a list of RA patients, and compared it with 1,000 sets of same-sized matched control groups. In addition, we estimated the kinship coefficient and risk ratios for relatives of the RA patients., Results: Several familial clustering tests demonstrated that the RA patients were more related to each other than were the average control set of Icelanders. A significantly fewer number of founders was necessary to account for our patient list than for the random sets of matched controls (P < 0.001), and the average pairwise identity-by-descent sharing was greater among the patients than among the control sets (P < 0.001). In addition, there was an increased risk of RA in first- and second-degree relatives of the patients; e.g., for siblings, the risk ratio was 4.38 (95% confidence interval 3.26-5.67), and for uncles/aunts, the risk ratio was 1.95 (95% confidence interval 1.52-2.43)., Conclusion: The familial component of RA is shown to extend beyond the nuclear family, thus providing stronger evidence for a significant genetic component to RA.

We have previously reported linkage of systemic lupus erythematosus to chromosome 2q37 in multicase families from Iceland and Sweden. This locus (SLEB2) was identified by linkage to the markers D2S125 and D2S140. In the present study we have analyzed additional microsatellite markers and SNPs covering a region of 30 cM around D2S125 in an extended set of Nordic families (Icelandic, Swedish, and Norwegian). Two-point linkage analysis in these families gave a maximum lod score at the position of markers D2S2585 and D2S2985 (Z = 4.51, PIC = 0.65), by applying a "model-free" pseudo-marker linkage analysis. Based on multipoint linkage analysis in the Nordic families, the most likely location of the SLEB2 locus is estimated to be in the interval between D2S125 and the position of markers D2S2585 and D2S2985, with a peak multipoint lod score of Z = 6.03, assuming a dominant pseudo-marker model. Linkage disequilibrium (LD) analysis was performed using the data from the multicase families and 89 single-case families of Swedish origin, using the same set of markers. The LD analysis showed evidence for association in the single-case and multicase families with locus GAAT3C11 (P < 0.0003), and weak evidence for association was obtained for several markers located telomeric to D2S125 in the multicase families. Thirteen Mexican families were analyzed separately and found not to have linkage to this region. Our results support the presence of the SLEB2 locus at 2q37.

Objective: To study MHC haplotypes and C4AQ0 in Caucasian multicase systemic lupus erythematosus (SLE) families from Iceland., Methods: Eight families with 26 SLE patients, 98 non-SLE first-degree relatives, and a control group were studied. For statistical analysis one SLE patient and one first-degree relative were randomly chosen from each family. C4 allotyping was performed by protein electrophoresis, HLA typing of class I by the lymphocytotoxicity test, and typing of class II alleles with polymerase chain reaction with sequence specific primers., Results: Six of the 8 families showed a high background of C4A protein deficiency (C4AQ0) and a significant increase was seen in C4AQ0 in the randomly chosen group of patients. A similar tendency that was statistically nonsignificant was seen in first-degree relatives. In the SLE patients C4AQ0 was found on several MHC haplotypes. Half the patients with C4A protein deficiency carry C4AQ0 on the classical C4A deletion haplotype B8-C4AQ0-C4B1-DR3 or variants of it, and the remaining C4A deficient patients on other non-DR3 carrying haplotypes. The transmission of C4AQ0 from parents to patients was in most cases through the family line, although in some instances it originates from outside the multicase SLE family through spouses married into the family., Conclusion: In these Caucasian multicase SLE families from Iceland, C4AQ0 shows weaker linkage disequilibrium with DR3 than reported in studies on other white populations, emphasizing the role of ethnicity. The common factor in the MHC haplotypes studied is C4AQ0, supporting a hypothesis that C4AQ0 may be an independent risk factor for SLE.

The genes coding for the two components of complement 4 (C4), C4A and C4B, are located within the major histocompatibility complex (MHC) on the short arm of chromosome 6. Several studies have shown that deficiency of C4A is associated with systemic lupus erythematosus (SLE), rheumatoid arthritis and scleroderma. A large deletion covering most of the C4A gene and the 21-hydroxylase-A (21-OHA) pseudogene found on the extended haplotype B8-C4AQ0-C4B1-DR3 is estimated to account for approximately two-thirds of C4A deficiency in Caucasian SLE patients. Detection of this C4A null allele has been technically difficult due to the high degree of homology between C4A and C4B, with protein analysis and restriction fragment length polymorphism (RFLP) analysis using Southern blotting being the only approaches available. In this study, a long PCR strategy was used to rapidly genotype for the C4A deletion through specific primer design. The methodology makes use of the unique sequence of the G11 gene upstream of C4A and the sequence of a 6.4 kb retrotransposon, the human endogenous retrovirus HERV-K(C4), which is present in intron 9 of C4A but absent in the case of the deletion.

To identify chromosomal regions containing susceptibility loci for systemic lupus erythematosus (SLE), we performed genome scans in families with multiple SLE patients from Iceland, a geographical and genetic isolate, and from Sweden. A number of chromosomal regions showed maximum lod scores (Z) indicating possible linkage to SLE in both the Icelandic and Swedish families. In the Icelandic families, five regions showed lod scores greater than 2.0, three of which (4p15-13, Z=3.20; 9p22, Z=2.27; 19q13, Z=2.06) are homologous to the murine regions containing the lmb2, sle2 and sle3 loci, respectively. The fourth region is located on 19p13 (D19S247, Z=2.58) and the fifth on 2q37 (D2S125, Z=2.06). Only two regions showed lod scores above 2.0 in the Swedish families: on chromosome 2q11 (D2S436, Z=2. 13) and 2q37 (D2S125, Z=2.18). The combination of both family sets gave a highly significant lod score at D2S125 of Z=4.24 in favor of linkage for 2q37. This region represents a new locus for SLE. Our results underscore the importance of studying well-defined populations for genetic analysis of complex diseases such as SLE., (Copyright 2000 Academic Press.)

Objective: To study the contribution of the IL10 gene to the susceptibility to systemic lupus erythematosus (SLE)., Methods: Analysis by fluorescent-semiautomated genotyping of a dinucleotide repeat located in the promoter region of the IL10 locus (microsatellite G)., Results: No significant difference was found in the frequencies of the microsatellite alleles of 330 Mexican patients with SLE compared to 368 controls from the same population. Two-point linkage analyses were carried out using 13 Mexican, 13 Swedish, and 8 Icelandic families with 2 or more cases with SLE. No linkage was revealed between IL10 and SLE, using a variety of parameter settings., Conclusion: Our results do not support that the IL10 gene contributes to the susceptibility to SLE in the populations we studied.

Objective: To evaluate the production of interleukin-10 (IL-10) as well as levels of IgG and antinuclear antibodies (ANA) in systemic lupus erythematosus (SLE) patients and their first-degree relatives and spouses in Icelandic SLE multicase families., Methods: IL-10 production was studied by enzyme-linked immunospot assay of freshly isolated peripheral blood mononuclear cells. Total IgG and ANA were also investigated. Subjects consisted of 23 SLE patients and 47 of their first-degree relatives in 9 Icelandic multicase families. Subjects were ethnically matched by a group of healthy controls. A separate study investigated 12 SLE patients (also from SLE multicase families) and their spouses and a matched group of healthy controls. A predefined protocol was used to obtain both clinical and laboratory data, including information about SLE and other autoimmune disorders., Results: The SLE patients had a significantly higher number of IL-10-producing cells compared with both first-degree relatives and healthy controls (P = 0.0005 and P < 0.0001, respectively). First-degree relatives also had a significantly higher number of IL-10-producing cells compared with healthy controls (P = 0.01). This was also true for the spouses of SLE patients, who had a higher number of IL-10-producing cells compared with matched healthy controls (P = 0.02)., Conclusion: SLE patients and their first-degree relatives, as well as a limited number of healthy spouses of SLE patients, had increased numbers of spontaneous IL-10-producing cells. These data support the hypothesis that IL-10 production may be genetically determined, and may predispose one toward development of SLE. This has previously been suggested by studies of SLE patients and their relatives in another ethnic population, using another method for measuring IL-10 production. Although these data are based on a small number of observations, they suggest that not only genetic but also environmental factors may be of importance in determining IL-10 production, since the spouses of SLE patients also had an increased number of IL-10-producing cells.

Systemic lupus erythematosus is a disease of unknown etiology. Multiple genetic factors are believed to be involved in its pathogenesis. In addition, and due to genetic heterogeneity, these factors and/or their combinations may be different in different ethnic groups, while some might be shared between populations. We have performed genome scans in multicase families from three different population groups, two from Northern Europe, with a high degree of homogeneity, and the third from a recently admixed population of Mexican Mestizos. Although our family material is relatively small, the results presented here show that using family sets from well defined populations are sufficient to detect susceptibility loci for SLE. Our results also reveal the chromosomal regions most likely to contain susceptibility genes for SLE., (Copyright 1999 Academic Press.)

Objective: To investigate the association of C4AQ0 with increased incidence of systemic lupus erythematosus (SLE) or positive serology (28%) in an extended Icelandic family, and whether this can be explained by impaired complement function in handling immune complexes (IC)., Methods: The ability of the classical pathway to opsonize nascent IC [alkaline phosphatase (AP)-anti-AP] and bind them to human erythrocytes was evaluated by the new ICRB assay. The capacity of erythrocytes from family members to bind nascent IC was also measured by a modification of the ICRB assay. IC levels were measured by complement consumption assay, C3d by a sandwich ELISA, factor B by immunoelectrophoresis, and the alternative pathway function by a hemolytic assay., Results: Family members with homozygous or heterozygous C4AQ0 (47%) showed no impaired complement dependent opsonization of IC and binding to erythrocytes. Their factor B and alternative pathway function was normal. Fifty-six percent of the family members (n=18) had abnormally high IC levels, seemingly independent of C4AQ0. However, 6 of the 7 individuals with high IC levels and SLE symptoms had C4AQ0 compared to 2 of 11 symptom-free individuals with high IC levels., Conclusion: Our results suggest that the susceptibility for SLE in this family may result from 2 different defects, one leading to elevated IC levels, and another associated with C4AQ0 without detectable impairment in the complement dependent IC transport mechanism. Individuals with both abnormalities have increased susceptibility to SLE.

Objective: To perform an exploratory analysis of the relative contribution of single MHC genes to the pathogenesis of systemic lupus erythematosus (SLE) in a homogenous white population., Methods: MHC class II alleles and C4 allotypes were determined in 64 SLE patients and in ethnically matched controls. HLA-DR and DQ typing was performed by polymerase chain reaction amplification with sequence specific primers. C4 allotypes were determined by agarose gel electrophoresis., Results: The frequency of C4A*Q0 was significantly higher in patients than in controls (46.9% v 25.3%, p = 0.002). HLA-DRB1, DQA1, and DQB1 alleles in the whole group of SLE patients were not significantly different from those of controls. On the other hand increase in DRB1*03 was observed in the group of patients with C4A*Q0, as compared with patients with other C4A allotypes (p = 0.047). There was no significant correlation between severe and mild disease, as judged by the SLEDAI, and HLADR, DQ alleles and comparing the patients with C4A*Q0 with those with other C4A allotypes there was no significant difference regarding clinical manifestations., Conclusion: The results are consistent with the argument that C4A deficiency contributes independently to susceptibility and the pathogenesis of SLE. C4A*Q0 in SLE patients in Iceland shows weaker linkage disequilibrium with DR3 genes than reported in most other white populations and emphasises the role of ethnicity.

Objective: To investigate whether participation of factor B (FB) in immune complex transport might explain long periods of clinical remissions in a homozygous C2-deficient patient with systemic lupus erythematosus (SLE) treated regularly with plasma infusions., Methods: Immune complex red cell binding (ICRB) was assayed as enzyme activity, C3d by enzyme-linked immunosorbent assay, and FB by immunoelectrophoresis., Results: C2-deficient sera showed low-grade ICRB, which correlated with levels of FB. This activity could be blocked with antibodies to C1q, C4, or FB, but not by antibodies to C2. C3d levels in the patient's plasma changed during infusion, followed by a gradient increase during remission. Comparison of ICRB, C3d, and FB suggested an inverse relationship between FB levels and clinical symptoms., Conclusion: In C2 deficiency, FB may interact with C4 to provide a low-grade ICRB. This activity could be clinically significant in patients with C2 deficiency and explain why they are less prone to SLE than patients with C1q or C4 deficiency.

Objective: To analyze the relationship between lymphocyte subsets, different rheumatoid factor (RF) isotypes, and clinical features in patients with rheumatoid arthritis (RA)., Methods: Patients with established RA (n = 95) were examined clinically and blood samples were collected for measurements of RF by ELISA and for analysis of lymphocyte subsets by flow cytometry., Results: IgA RF positive patients had more severe disease and higher prevalence of extraarticular manifestations than the other patients. Patients with elevated IgA RF had a higher percentage of CD5+ B cells and of CD4+CD45RO+ T cells compared to the other patients with RA or controls. High percentage of CD4+CD45RO+ T cells was also significantly associated with extraarticular manifestations. Patients with the sicca syndrome had significantly higher ratio of CD5+ B cells than patients without or with other types of extraarticular manifestations., Conclusion: Different disease manifestations in RA may be associated not only with certain RF isotypes and RF isotype combinations but also with changes in lymphocyte subsets in the blood. The relative increase of CD4+CD45RO+ T cells in the blood of IgA RF positive patients with RA might reflect preferential recruitment of CD8+CD45RO+ T cells to inflammatory sites.

Introduction: There has been substantial difference in the reported frequency of neuropsychiatric manifestations in systemic lupus erythematosus (SLE). This difference can at least partly be explained by methodological difference, especially in case identification., Material and Methods: A retrospective study in a group of 65 unselected SLE patients was performed. The study consisted of two parts: 1) a neuropsychiatric evaluation which included a review of the patient's charts and a neurological interview, 2) a structured psychiatric interview, i.e. the Diagnostic Interview Schedule., Results: In part one 37 patients or 57% had positive findings, while in part two the number was 32 pa nottients or 49%. Overall, 46 patients or 71% had experienced one or more neuropsychiatric manifestations. The most prevalent manifestations in part one were headache and psychoses, and in part two simple phobia, agarophobia, social phobia and generalized anxiety. Approximately 25% of the patients were treated solely outside hospitals., Conclusion: The unselected nature of this study gives a picture probably more representative of the true neuropsychiatric involvement in systemic lupus erythematosus than previous studies of selected patient populations.

Objective: In an epidemiological survey of systemic lupus erythematosus (SLE) in Iceland several families with multiple cases were identified. In one family, 35 individuals (family members and spouses) in 3 generations were studied clinically, tested for autoantibody formation, and typed for HLA and toxicity complement phenotypes., Methods: Typing for HLA-A, B, C, DR, and DQ was performed by microlymphocytotoxic assay. In selected samples HLA-DR typing by polymerase chain reaction amplification with sequence specific primers was performed. C4 allotypes were defined by agarose gel protein electrophoresis followed by immunofixation with goat antisera., Results: Five family members fulfilled 4 or more criteria for SLE. Additionally, 5 family members had clinical manifestations or positive serology but did not fulfill 4 ARA criteria. The mean age at onset of symptoms was 22 yrs (8-40). Other autoimmune diseases were not documented in family members. C4A null seemed to be highly associated with disease in this family. All except one patient with SLE and all those with clinical manifestations and positive serology had C4A null in the homozygous or heterozygous form. The individual with SLE and not carrying C4A null had both HLA haplotypes identical. It is noteworthy that there were 5 different C4A null bearing haplotypes involved, of which 3 originated from the spouses., Conclusion: Our results are consistent with the argument that C4A deficiency plays a role in the pathogenesis of SLE. There is, however, the possibility of an unidentified environmental or another genetic factor being involved.

In rheumatoid arthritis (RA) seropositivity has been associated with poor prognosis including bone erosions and extra-articular manifestations. However, findings have been conflicting on the association between individual rheumatoid factor (RF) isotypes and extra-articular manifestations. In this study the occurrence of extra-articular manifestations was examined in the context of the RF isotype patterns rather than individual RF isotypes. IgM, IgG and IgA RF was measured by ELISA in 74 patients with RA and the findings correlated with the presence or absence of extra-articular manifestations. Of the IgA RF positive patients 80% had one or more extra-articular manifestations. In contrast, only 21% of patients with raised IgM and/or IgG RF but normal IgA RF had some extra-articular manifestations and 27% of the seronegative patients. It is concluded that the previously reported association between raised RF and extra-articular manifestations in RA can largely be attributed to the IgA RF isotype.

Objective: To investigate the incidence and clinical and histopathologic features of giant cell (temporal) arteritis (GCA) in the Caucasian population of Iceland., Methods: All patients diagnosed between 1984 and 1990 were included. Case ascertainment for the study was done in 2 ways: 1) a computerized search from all hospitals and primary care clinics for the diagnosis of GCA, and 2) a review of all temporal artery biopsies performed during the 7-year period., Results: One hundred thirty-three patients with GCA were identified. All fulfilled the 1990 American College of Rheumatology criteria for the classification of GCA. The incidence rate for the population 50 years and older was 27/100,000 (36/100,000 and 18/100,000 for women and men, respectively). Clinical findings included the following: mean age at diagnosis 72.5 years for women and 70.3 years for men, new headache 63.2%, abnormal temporal artery on palpation 43.6%, mean erythrocyte sedimentation rate 88 mm/hour, symptoms of polymyalgia rheumatica 48.1%, and visual disturbances 14.3%. A total of 744 patients underwent temporal artery biopsy during the 7-year period; 16.8% had a positive biopsy result. All 133 patients with the diagnosis of GCA underwent a temporal artery biopsy; 94% had a positive result. Histopathologic findings from the positive biopsies included a fragmented internal elastic lamina in 99.2%, giant cells in 65.6%, and fibrinoid necrosis in 12%., Conclusion: Compared with previous epidemiologic surveys, this study shows a high incidence of biopsy-proven GCA in Iceland.

The diffuse connective tissue diseases constitute a group of inflammatory diseases with the potential of involvement of many organ systems. The etiopathogenesis is thought to be multifactorial, involving the interaction between particular genetic background and exogenous agents. Recently theories regarding inherited defects in the clearing of immune complexes have been put forward. Serological markers are important diagnostic tools in many of these diseases and emphasize the role of autoimmunity. Epidemiological studies have demonstrated an increase in incidence in some of these diseases and because of selection bias many epidemiological studies may overestimate the severity of these diseases. Therapy aims at modulating and suppressing inflammation. A step towards more directed immune modulation is the use of cyclosporin A and monoclonal antibodies against various surface antigens and mediators in inflammation.

We have examined the effects of hereditary homozygous C2 deficiency on the processing of radiolabeled soluble immune complexes (IC). A patient with C2 deficiency was studied before and after treatment with fresh frozen plasma (FFP). Hepatitis B surface Ag (HBsAg):anti-HBsAg immune complexes were prepared in vitro using Ag radiolabeled with 123I, and injected intravenously. Dynamic and static gamma-scintigraphy was performed to delineate the sites and kinetics of complex clearance. The patient was initially studied when her C2 level and CH50 were zero, and again 1 wk later after treatment with 12 units of FFP, which normalized these parameters. Before treatment there was rapid uptake of complexes by the liver (t90% [time for 90% uptake] = 13.6 min) and rapid clearance from the circulation (t1/2 = 6.8 min). No splenic uptake was detected, and there was no binding of complexes to erythrocyte CR1. Between 30 and 60 min there was release of 11% of the tracer from the liver. In the second study, performed after normalization of classical pathway complement activity, the t1/2 of IC clearance increased to 9.8 min, and t90% was 27 min. Twenty percent of injected complexes now localized to the spleen, and there was no longer any release of complexes between 30 and 60 min. The kinetics of IC processing and the sites of uptake in this posttherapy study were closely similar to two normal subjects studied in parallel, with a maximum of 72% of injected complexes binding to erythrocytes. These observations indicate that the uptake of immune complexes in the spleen in humans is complement-dependent, and suggest that the observed predisposition to SLE in patients with complement deficiency may be related to abnormal processing of immune complexes.

Histological changes in biopsies from the placental and placental bed in 2 successive pregnancies of 2 women with systemic lupus erythematosus and antiphospholipid antibodies were studied. In one of the first 2 pregnancies vasculitis was found in the spiral arteries of the placental bed biopsy, while the other showed perivascular inflammatory infiltration and deciduitis. This was associated with poor pregnancy outcome and elevated antiphospholipid antibodies (aPL). In the subsequent 2 pregnancies prednisolone treatment was tailored to suppress the aPL titer with markedly decreased inflammatory changes and no evidence of vasculitis in the spiral arteries of the placental bed was found. This was associated with a normal pregnancy outcome. A causal relationship between aPL and inflammatory vascular changes in the placental bed as well as a beneficial effect of the corticosteroid treatment in those two women in suggested.

Although systemic lupus erythematosus (SLE) is abnormally common in individuals with complement deficiency, conclusive evidence has been lacking for a direct causal relationship between disease manifestations and a missing complement component. A patient with C2 deficiency and SLE has been treated with 56 courses of fresh frozen plasma (FFP) infusions over a period of 8 years. Each infusion, involving a total of 12 units of FFP administered in equal doses over 4 consecutive days, has consistently resulted in a transient restoration of the classical pathway of complement, and a full clinical remission lasting 6-8 weeks. This report is concerned with changes in the levels of immune complexes, C2 and C3d during an infusion cycle. Four progressively rising peaks in C2 and C3d were observed during the 4 days of the plasma infusion, and these peaks coincided with four reciprocally descending troughs in the levels of immune complexes. Identical fluctuations have been consistent in all the plasma-infusion cycles that have so far been monitored, and their consistent association with clinical remissions indicates a causal relationship between the C2 restoration and clinical remissions in this C2-deficient SLE patient.

In a nationwide study the 1982 revised ARA criteria were applied for the classification of systemic lupus erythematosus (SLE). This unselected group of patients included all cases diagnosed and managed in hospitals, as well as outside hospitals in Iceland over the 10-year period from 1975 to 1984. Seventy-six new cases were found, with an incidence of 5.9 and 0.8/100,000 for females and males at risk, respectively. The mean age at diagnosis was 46.6 years. Twenty-five percent of the patients would have been missed had the study included hospital patients only. A clinical pattern different from previous studies was found as illustrated by a low incidence of kidney disease; nephritis was found in 20% of patients. Comparison with a former study on SLE in Iceland shows an actual increase in incidence over a period of 10 years. The 5 year survival was 84% and the 10 year survival 78%.

Eight patients with psoriatic arthritis entered an open study to determine the efficacy of oral cyclosporin A for their treatment. The starting dose was 3.5 mg/kg daily. Findings after the first six months are reported. One patient withdrew from the study after five months because of tremors, general malaise, and lack of improvement. Seven patients continued through the study, and marked improvement was found after two months in all clinical indices. The skin lesions improved in a parallel fashion. The cyclosporin A dose had to be reduced temporarily by 25% in three patients because of an increase in serum creatinine of more than 50%. A rise in diastolic blood pressure in three patients responded to treatment. The study suggests that cyclosporin A effectively treats arthritic manifestations of psoriasis as well as psoriatic skin lesions.

Plasma and serum samples from a patient with homozygous C2 deficiency and severe systemic lupus erythematosus who responded with full clinical remission after plasma infusions were examined for immune complexes (IC), C3 activation products, and the terminal complement complex (TCC). Plasma contained large amounts of C4-containing IC but no C3-containing IC or complement activation products. Classical pathway activation in vitro did not lead to C3 activation or TCC formation as seen in normal serum, but a very efficient binding of C1q and C4 was found. No disturbances in alternative pathway activation were observed. The results indicate an impaired formation of C3-containing IC and an inefficient clearance of C4-containing IC, supporting the idea of a causal relationship between the dysfunctional classical pathway, pathophysiology, and clinical manifestations in this patient.

A systematic analysis of the efficacy of methotrexate (MTX) in severe rheumatoid arthritis (RA) was carried out. Twenty-one patients with severe classical RA resistant to conventional therapy were treated with 7.5 to 25 mg of oral or intramuscular MTX for 3-114 weeks (mean of 38 weeks). Eleven patients (52.4%) showed definite clinical improvement and a fall in sedimentation rate; some improvement was seen in 5 other patients (23.8%). Two patients were unresponsive. Three patients discontinued MTX, 1 because of acute hepatitis and the other 2 because of noncompliance and fear of toxicity. Abnormal liver function tests reversible with modification of therapy occurred frequently. Other side effects were minor. The results of this uncontrolled study indicate that MTX may be an effective drug for the treatment of severe RA. Double blind trials and longterm followup are needed prior to its widespread use in RA.

We report a case of systemic lupus erythematosus (SLE) and recurrent infections associated with isolated Clq deficiency. A 17-year-old girl from Saudi Arabia was hospitalized with seizures, fever, arthralgia, hair loss, oral ulceration and skin rash. Clinical and laboratory findings fulfilled the ARA preliminary criteria for the classification of SLE. Nonlesional skin contained immunoglobulins and C3 at the dermal-epidermal junction. She did not have antibodies to DNA or low C3 or C4. Total serum hemolytic complement activity was absent due to a total selective absence of Clq. There was no circulating inhibitor of Clq activity. The published experience of isolated selective complete Clq deficiency associated with clinical disease is reviewed.

We describe a patient with C2 deficiency and severe systemic lupus erythematosus (SLE) that did not respond to conventional therapy. Over a period of 45 months, she was given 22 cycles of plasma therapy. For 6-8 weeks after each plasma infusion, there was a full clinical remission of the SLE, and a brief restoration of hemolytic complement activity. However, there were more prolonged increases in the activities of the complement components that are believed to be more directly involved in the clearance of immune complexes. Because of the theoretical risk that the infused complement might enhance inflammatory tissue damage, there has been some reluctance to try plasma replacement therapy in SLE patients with complement deficiency. We have not observed any adverse effects with the long-term use of this treatment, and our experience indicates that this therapeutic approach can be beneficial.