Interleukin-18 as an efficient marker for remission and follow-up in patients with inactive adult-onset Still's disease.

OBJECTIVES: Diagnosis of adult-onset Still's disease (AOSD) is difficult because of a lack of pathognomonic findings and markers. The aim of this study was to investigate the efficacy of interleukin (IL)-18 and free IL-18 in the diagnosis and follow-up of patients with AOSD. METHOD: Levels of inflammatory cytokines, IL-18, IL-18 binding protein (IL-18BP), and free IL-18 were compared in 80 AOSD patients and 90 controls. The AOSD patients were divided into active and inactive groups according to disease activity, and the inactive patients were subdivided into a remission subgroup and a low disease activity subgroup. We compared erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferritin, IL-18, and free IL-18 as disease activity markers in the AOSD patients. Serial serum levels of activity markers were measured in 52 of the 80 AOSD patients at 3- to 6-month intervals. RESULTS: There were significantly higher levels of IL-18 and free IL-18 in the AOSD patients than in the controls. IL-18 and free IL-18 were significantly higher in the active group than the inactive group (p < 0.001 for all). Unlike other activity markers, IL-18 and free IL-18 levels in the low disease activity subgroup were significantly higher than those in the remission subgroup within the inactive group (p = 0.004 and 0.005, respectively). During serial follow-up, ferritin and IL-18 showed a significant decrease in the responder and remission subgroup. CONCLUSIONS: IL-18 might be an efficient marker for diagnosis and follow-up of AOSD and might also be a useful predictor of remission, especially in clinically inactive patients.

Clinical implication of extended-spectrum cephalosporin nonsusceptibility in Streptococcus pneumoniae meningitis.

The clinical implication of extended-spectrum cephalosporin (ESC) resistance has been unclear in patients with Streptococcus pneumoniae meningitis (SPM). We collected the clinical data of 120 patients with SPM in 12 hospitals of the Republic of Korea. The clinical characteristics and outcomes of 23 ESC-nonsusceptible SPM episodes were compared to those of 97 ESC-susceptible episodes. Hospital acquisition, presence of other foci of pneumococcal infection, septic shock at initial presentation, or concomitant bacteremia were more commonly observed in ESC-nonsusceptible than ESC-susceptible SPM. Empiric antimicrobial therapy with vancomycin and ESC combination was very common in both groups. Although there was a tendency towards higher early fatality in ESC-nonsusceptible SPM (3-day mortality; 17.4 % vs. 4.4 %, p = 0.05), in-hospital mortality (26.1 % vs. 20.9 %, p = 0.59) and median length of hospital stay (20 days vs. 24 days, p = 0.34) did not differ between ESC-nonsusceptible and ESC-susceptible SPM.

Thiopurine S-methyltransferase polymorphisms and the relationship between the mutant alleles and the adverse effects in systemic lupus erythematosus patients taking azathioprine.

OBJECTIVE: The present study sought to elucidate the genetic basis of thiopurine methyltransferase (TPMT) polymorphism and subsequently to investigate the relationship between mutant TPMT and an adverse response observed in Korean patients with systemic lupus erythematosus (SLE) taking azathioprine (AZA). METHODS: The TPMT genotype of 342 patients with SLE was determined by MALDI-TOF mass spectrometry and correlated with the effects of clinical exposure to AZA. RESULTS: TPMT polymorphism was detected in 17 of the 342 study subjects (5.0%), 12 heterozygous for the TPMT*3C allele and 5 heterozygous for the TPMT*6 allele. Numerous patients taking AZA demonstrated adverse drug responses. Severe nausea occurred in 4 patients with the TPMT*3C allele, while 1 patient with the TPMT*6 allele suffered severe bone marrow toxicity. Leucopenia (n = 17), nausea (n = 4), and abnormal liver function (n = 1) were suspected in 23 of the 94 lupus patients taking AZA. AZA was relatively well tolerated by the remainder of the patients. The heterozygous genotype for the TPMT*3C and *6 alleles was frequently detected in Korean SLE patients. CONCLUSION: Contrary to previous hypotheses, this study identified no statistical correlation between TPMT genotype and AZA toxicity. We thus conclude that TMPT genotyping cannot replace regular blood monitoring in SLE patients receiving AZA treatment.

A case report: isolated a heavy chain monoclonal gammopathy in a patient with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin change syndrome.

A 45-year-old South-Korean man presented with abdominal distension, progressive paresthesia and motor weakness of both lower extremities. Our case was identified as polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin change (POEMS) syndrome based on diagnostic criteria. Circulating M components of POEMS syndrome consist mainly of IgG or IgA-lambda and rarely IgM-lambda, IgG-kappa or isolated light chains. In this case, the M-band on serum protein electrophoresis and isolated IgA heavy chain on serum immunofixation electrophoresis were demonstrated, but there was no abnormal light chain. We suggest that this case may be associated with a pattern of abnormal secretion of monoclonal protein or a coincidence of a heavy chain disease in POEMS syndrome, even though the latter possibility may be very rare.

Successful treatment of protein-losing enteropathy due to AA amyloidosis with somatostatin analogue and high dose steroid in ankylosing spondylitis.

Secondary amyloidosis is an occasional complication of ankylosing spondylitis (AS) and in most cases renal amyloidosis presents with proteinuria, nephrotic syndrome and decreased renal function. We describe a 32-year-old male patient with AS manifested by frequent diarrhea, intermittent abdominal pain and low serum albumin levels. He has suffered from severe inflammatory back pain for 14 years with multiple peripheral joint involvement. Protein-losing enteropathy due to gastrointestinal amyloidosis was diagnosed with 99mTc-human albumin scintigraphy, fecal alpha-1 antitrypsin clearance and colonoscopic biopsy with Congo red staining. Somatostatin analogue octreotide and prednisolone were introduced with successful result.

The incidence and clinical characteristics of Mycobacterium tuberculosis infection among systemic lupus erythematosus and rheumatoid arthritis patients in Korea.

OBJECTIVES: The aim of this study was to describe the incidence and clinical characteristics of Mycobacterium tuberculosis infection in SLE and RA patients in Korea where the prevalence rate of active pulmonary tuberculosis in a general population is relatively higher than in Western countries. PATIENTS: We reviewed the medical records of 283 SLE and 284 RA patients retrospectively and then assessed the incidence, risk factors, and clinical characteristics of active tuberculous infection. We then compared the results for the two different groups. RESULTS: Tuberculosis was documented in 15 SLE and 7 RA patients with an incidence rate of 7.9/1,000 patient-years and 2.3/1,000 patient-years, respectively (p = 0.003). SLE-associated tuberculosis cases included 3 of miliary tuberculosis, 7 of pulmonary tuberculosis (including 1 case of diffuse pulmonary involvement with meningitis) predominantly involving two or more lobes at the mid-/lower lungfield, and 5 extra-pulmonary forms (joint, bone, kidney, larynx, pleura). All of the RA-associated tuberculosis cases were pulmonary forms with the majority being localized to single lobe, and only one case had a past history of tuberculosis, whereas a past history of tuberculosis and a longer duration of the underlying disease were significantly correlated with the development of tuberculosis in the SLE patients. Major organ involvement, the mean daily dosage of prednisolone, and a history of over 30 mg of daily prednisolone were not related to the development of tuberculosis. However, when we took only those patients taking corticosteroid until the diagnosis of tuberculosis for analysis, SLE patients with tuberculosis showed a higher daily dosage of prednisolone than those without tuberculosis. CONCLUSION: Taken together, the characteristics of tuberculosis in SLE patients were: (1) a higher incidence rate, (2) more frequent extra-pulmonary involvement, (3) more extensive pulmonary involvement, and (4) a higher relapse rate than in rheumatoid arthritis. Thus, the contributory role of M. tuberculosis infection in the morbidity and mortality of patients with SLE must be emphasized, especially in areas in which this bacteria is endemic.

Coexistence of coronary aneurysms and total occlusion of coronary arteries in systemic lupus erythematosus.

A 22-year-old woman with known SLE and chronic hepatitis B developed anginal pain. During this period there was serologic but no other clinical evidence of active SLE. Myocardial perfusion SPECT showed a severe reversible perfusion defect in the posterior wall, and coronary angiography revealed multiple coronary aneurysms in the left anterior descending artery and circumflex artery and total occlusion of the proximal right coronary artery. This case suggests that coronary aneurysms and total occlusion may represent a sequela of arteritis, or of a combination of underlying vasculitis and a recent thrombotic obstruction due to antiphospholipid syndrome.

High toxicity of sulfasalazine in adult-onset Still's disease.

OBJECTIVE: Sulfasalazine (SSZ) is an anti-rheumatic drug that has been used to treat chronic arthritis. In many reports, the use of SSZ in children with systemic onset juvenile rheumatoid arthritis (JRA) revealed frequent side effects which required discontinuation of the drug. We examined whether there were frequent side effects of SSZ in patients with adult-onset Still's Disease (AOSD). METHODS: From July 1990 to April 1998, we followed 41 AOSD patients. Ten were given SSZ for the treatment of arthritis and the side effects were studied. We also studied 109 consecutive patients with RA who had been given SSZ, as a control group. In addition, we retrospectively studied the side effects and efficacy of SSZ in both groups through their medical records. RESULTS: Six patients (60%, p < 0.01) with AOSD experienced side effects ranging from mild ones like abdominal pain, nausea and vomiting, urticaria, and facial flushing to severe ones such as high fever, hypotension, and severe myelosuppression as well as fulminant hepatitis, which led to the death of one patient. However, 16 patients (14.7%) with RA stopped using SSZ due to mild side effects such as rash, urticaria, gastrointestinal troubles, mild leukopenia, and fever. Three AOSD patients (30%, p = 0.053) and 15 RA patients (13.8%) stopped using SSZ due to its inefficacy. CONCLUSION: We conclude that SSZ appears to have frequent severe side effects in AOSD, as in systemic onset JRA. These potential adverse effects of SSZ should be considered when it is used to treat chronic arthritides with systemic symptoms. Further study of SSZ in the treatment of AOSD in a multi-center, placebo-controlled environment is needed.

Transverse myelitis in a patient with long-standing ankylosing spondylitis.

Ankylosing spondylitis is reported to involve not only the joints but other organs as well. Among these extra-articular involvements, uncommon complications associated with nervous system such as single root lesions, compression of the myelum and cauda equina syndrome have also been documented. Here we present a patient with long-standing ankylosing spondylitis who developed spastic paraparesis. Extensive study to find the cause of a spastic paraparesis failed and therefore led to the conclusion that this patient was suffering from transverse myelitis. Similar reports in the past have been attributed to an association with multiple sclerosis; however, we suggest that the findings support the diagnosis of a rare complication of ankylosing spondylitis with an unknown etiology.

Association between HLA-DR B1 and clinical features of adult onset Still's disease in Korea.

OBJECTIVE: To determine whether HLA-DR alleles are associated with the development and clinical features of Adult Onset Still's Disease (AOSD) in Korea. METHODS: Forty-seven patients (41 women, 6 men, mean age at diagnosis 31.6 yr) meeting Yamaguchi's criteria for AOSD and 144 healthy controls were enrolled in this study. The patients with AOSD were subdivided into groups according to their chronicity: monocyclic systemic, polycyclic systemic, and chronic destructive type, and were furthermore classified as non-articular, oligoarticular or polyarticular types (having arthritis involving 5 or more joints) according to the extent of articular involvement. HLA-DRB1 genotypes were assessed by PCR-SSOP. RESULTS: Patients with AOSD had more frequent DRB1*12 (p = 0.028, relative risk (RR) = 2.27, 95% confidence interval (CI): 1.08-4.80) and DRB1*15 (p = 0.013, RR = 2.16, 95% CI: 1.17-4.00). They had less frequent DRB1*04 (p = 0.006, RR = 0.35, 95% CI: 0.16-0.75) compared to controls. DRB1*14 (p = 0.011, RR = 3.80, 95% CI: 1.27-11.31) were associated with the monocyclic systemic type. CONCLUSION: Korean AOSD patients had more frequent DRB1*12 and DRB1*15, and less frequent HLA-DRB1*04. The patients with the monocyclic systemic type had more frequent DRB1*14 alleles. This study suggests that Korean AOSD patients have distinct immunogenetic profiles, and that it would be valuable to assess the relationships between HLA-DRB1 genes and polymorphisms of proinflammatory cytokines in the pathogenesis of AOSD.

Seronegative spondyloarthropathy initiated by physical trauma.

We undertook this study to demonstrate the pattern of onset and the course of arthritis on the traumatised joint in spondyloarthropathy (SpA) initiated by physical trauma. Among 288 patients with SpA, 12 (4.2%) whose arthropathies were associated with trauma were reviewed retrospectively. There were seven patients with ankylosing spondylitis (AS), three with juvenile onset AS and two undifferentiated SpA. The type of trauma was direct injury to the joint and injuries at other sites, except in spinal surgery, for example. In eight cases the initial evidence of disease was peripheral arthritis. The disease first occurred in traumatised joints in five cases. Only three cases showed recurrent inflammatory episodes in the traumatised joints throughout the disease course. SpA initiated by trauma initially manifested as peripheral arthritis at the traumatised joints in about half of the cases. Inflammatory episodes preferentially involved other joints apart from the traumatised joints throughout the whole course of the disease.

Mixed connective tissue disease associated with skin defects of livedoid vasculitis.

A 21-year-old woman who had a 2-year history of mixed connective tissue disease (MCTD) developed rapidly evolving ulcers consistent with livedoid vasculitis (LV) in all distal extremities. She presented clinically with Raynaud's phenomenon, polyarthritis and swollen hands; serologically with high titres of ANA and anti-nRNP; and immunogenetically with HLA-DR4 and HLA-DR53. Although there was initial success in treatment except for the skin defects over the ankles, the patient died from disseminated intravascular coagulation. We suggest that LV may be a poor prognostic manifestation in MCTD.

Induction of remission with intravenous immunoglobulin and cyclophosphamide in steroid-resistant Evans' syndrome associated with dermatomyositis.

Evans' syndrome is characterised by the simultaneous or sequential occurrence of Coombs'-positive haemolytic anaemia (AIHA) and immune thrombocytopenia without underlying aetiology. It has been found to be associated with collagen vascular diseases, especially systemic lupus erythematosus (SLE) and scleroderma. However, Evans' syndrome with dermatomyositis is very rare. A 59-year-old woman, who had been taking high-dose prednisolone for a month and cyclosporin for 10 days for dermatomyositis, developed purpura on the left popliteal fossa. The platelet and haemoglobin levels decreased to 77,000/mm3 and 9.8 g/dl, respectively. Antiplatelet antibody was positive. Thrombocytopenia responded to intravenous immunoglobulin (IVIG) for a short time, but further decreased in a week. Her blood film showed features of haemolytic anaemia. Laboratory findings showed reticulocytosis and a positive direct Coombs' test. Bone marrow examination showed a mild hyperplasia of erythroid precursors and megakaryocytes. The patient was successfully treated with cyclophosphamide in addition to oral prednisolone. AIHA in connective tissue disease may develop gradually and show a benign clinical course in most patients. Therefore, we suggest that patients with dermatomyositis and anaemia should always be checked for haemolysis if there is no other explanation.

Quality of marital life in Korean patients with spondyloarthropathy.

The objectives of this study were to assess the quality of marital life (QML) in patients with spondyloarthropathy (SpA) in Korea and to identify possible gender differences in QML in patients with SpA. This was a case-control study at the outpatient unit of a tertiary care medical centre. Subjects were the patient group, composed of 47 married patients with SpA, and a comparison group composed of 47 healthy married adults with similar demographic characteristics. QML was measured using the Marital Satisfaction Inventory, Revised. As a result, QML was similar for both the male patients and the healthy men. However, the female patients had higher scores on the global distress scale (59.8 +/- 6.3 vs. 53.8 +/- 5.6, P=0.021) and the aggression scale (50.5 +/- 7.9 vs. 44.3 +/- 5.4, P=0.016) than the female comparison group. At the same time, the female patients demonstrated higher scores on the global distress scale (59.8 +/- 6.3 vs. 54.7 +/- 7.2, P=0.035) than the male patients. In conclusion, QML in Korean males with SpA was not greatly different from that of the male comparison group. However, QML in the female patients was characterised by higher global distress and a higher probability of aggression from their partner, but no significant sexual dissatisfaction.

A case of Dowling-Degos disease suggesting an evolutional sequence.

We report a 47-year-old woman who presented with asymptomatic reticulate hyperpigmentations on the neck, lateral face, axillae, trunk, inguinal areas, and dorsa of both hands and feet. We thought it was an unusual case in the spectrum between the pole of Dowling-Degos disease (DDD) and that of reticulate acropigmentation of Kitamura (RAK). Another interesting point was that the biopsied specimens from the abdomen, neck, and axillary lesions showed somewhat different histopathologic features from typical DDD, suggesting an evolutional sequence. From these findings we suggest that a lichenoid inflammation may be responsible for the typical maculo-papular lesions of DDD.

Association between the HLA-DRB1 gene and clinical features of systemic sclerosis in Korea.

OBJECTIVE: To determine whether HLA-DR alleles are associated with the development and clinical features of systemic sclerosis (SSc) in Koreans. METHODS: Seventy-nine patients (74 women and five men; 45 diffuse types and 34 limited types; mean age at diagnosis 43.9 years) fulfilling the American College of Rheumatology (ACR) classification criteria for SSc were enrolled. The controls were 144 healthy, disease-free Koreans. HLA-DRB1 genotypes were assessed by the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. RESULTS: The HLA-DRB1*15 allele was increased in anti-topoisomerase I autoantibody (anti-topo I)-positive SSc patients [p = 0.003, p corrected (p(corr)) = 0.039, odds ratio (OR) = 3.43, 95% confidence interval (CI) 1.45-8.13] compared with controls. The DRB1*11 allele was also observed more frequently in anti-topo I-positive SSc than in controls (13.3% vs. 4.2%) but not statistically significant (p = 0.053, p(corr) = 0.689). In patients with SSc, the DRB1*04 allele was associated with subcutaneous calcinosis (p = 0.048, OR = 4.56, 95% CI 1.07-19.37). Patients with overlap syndrome showed a negative association with the DRB1*04 allele (p = 0.036, OR = 0.26, 95% CI 0.08-0.91). CONCLUSION: The HLA-DRB1*15 allele was associated with the development of anti-topo I-positive SSc in Koreans. In addition, the DRB1*04 allele was associated with certain clinical features in SSc patients.

SLC11A1 gene polymorphisms in Korean patients with Behçet's disease.

OBJECTIVE: To investigate the potential susceptibility to the solute carrier family 11 member 1 (SLC11A1) gene polymorphisms of Korean patients with Behçet's disease (BD). METHODS: Ninety-nine patients with BD and 98 controls were recruited. Analyses of three polymorphisms of the SLC11A1 gene [the 5'-promoter (GT)n, D543N and A318V] were performed, either by denaturing high-performance liquid chromatography for D543N and A318V or by using automatic DNA sequencing for the (GT)n. The genotypes and alleles between patients with BD and the controls were compared using the chi2 test and Yate's correction test. RESULTS: No significant differences were found in the distribution of genotypes and alleles of the (GT)n polymorphism between BD patients and the controls. However, subjects with the allele 3 or the genotype allele 3/allele 3 of this polymorphism had a significantly lower risk of developing BD than those without this allele or genotype [allele: p = 0.029, pc = 0.039, odds ratio (OR) = 0.60, 95% confidence interval (CI) 0.37-0.95; genotype: p = 0.036, pc = 0.048, OR = 0.54, 95% CI 0.31-0.96]. In addition, the distributions of genotypes and alleles of D543N were similar between BD patients and controls (p>0.05). In the case of A318V, all of the BD patients and controls had a wild-type genotype. CONCLUSION: The allele 3 and the genotype allele 3/allele 3 of the 5'-promoter (GT)n in the SLC11A1 gene may have a protective effect for the development of BD in the Korean population. Further studies in other populations are required to confirm our results.

Palisaded neutrophilic granulomatous dermatitis presenting as an unusual skin manifestation in a patient with Behçet's disease.

A 32-year-old Korean woman with painful oral ulcers and a sore throat presented with multiple erythematosus papules on both legs. Histological examination of the papular lesions on the legs demonstrated palisaded granuloma with degeneration of collagen fibres in the dermis, compatible with palisaded neutrophilic granulomatous dermatitis (PNGD). This condition is known to be an unusual disease entity associated with various systemic autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, other connective tissue diseases, and systemic vasculitis. To our knowledge a case with typical Behçet's disease coinciding with PNGD among systemic autoimmune diseases has not been described before.