Abstract Objective To describe the clinical and laboratory features and natural history of the disease in systemic sclerosis (SSc; scleroderma) patients with anti–topoisomerase I (anti–topo I) antibody who have different skin thickness progression rates (STPRs). Methods SSc patients (n = 212) who were anti–topo I antibody positive were divided into 5 subgroups based on STPRs. Skin thickness was measured using the modified Rodnan skin thickness score (MRSS). Anti–topo I IgG antibody levels were determined. Results Sixty patients who were anti–topo I antibody positive had diffuse cutaneous SSc (dcSSc) with rapid progression, 82 had dcSSC with intermediate progression, and 29 had dcSSc with slow progression, 14 had limited cutaneous SSc (lcSSc) that became dcSSc, and 27 had lcSSc that did not change throughout. Patients beginning with lcSSc were younger at disease onset and had longer disease duration when diagnosed as having SSc. Interstitial lung disease was common and was equally distributed across the subgroups. Renal crisis occurred most often in patients with rapid progression (22%) and was absent in lcSSc patients. Cardiac involvement was most frequent in the dcSSc subgroups. Both kidney and heart disease occurred most often within 3 years after the onset of skin thickening. The 10‐year cumulative survival rate was <40% for patients with rapid and intermediate progression. Renal and cardiac causes of death were disproportionately frequent in these 2 subgroups. Anti–topo I antibody levels correlated with the STPR and the MRSS. Conclusion Anti–topo I antibody–positive patients with SSc with a rapid STPR have reduced survival rates, primarily due to early and often fatal renal and cardiac involvement. Anti–topo I antibody levels parallel the MRSS at the first visit and the STPR. This information is important for managing physicians and researchers planning clinical trials involving patients with early dcSSc.
Abstract Objective To describe the classification, demographic and clinical features, and survival in anti–U3 RNP autoantibody–positive patients with systemic sclerosis (SSc). Methods Medical records of 108 anti–U3 RNP–positive and 2,471 anti–U3 RNP–negative SSc patients first evaluated during 1985–2003 were reviewed. Anti–U3 RNP antibody was detected by protein and RNA immunoprecipitation. Disease classification, demographic and clinical features, organ system involvement, and survival were compared between the 2 patient groups, by Student's t ‐test, chi‐square analysis, and Mantel‐Haenszel test. Results The anti–U3 RNP–positive group had a higher proportion of African American patients (27% versus 5%; P < 0.001) and male patients (29% versus 19 % ; P = 0.021), and was younger at the time of first physician diagnosis (mean age 42.8 years versus 47.4 years; P = 0.001). The 2 groups had similar proportions of patients with diffuse cutaneous involvement (47% and 45% in those with and those without anti–U3 RNP, respectively). However, among patients with diffuse cutaneous involvement, the mean maximum modified Rodnan skin score was significantly lower in the anti–U3 RNP group (22.3 versus 27.9; P < 0.001). Skeletal muscle involvement was more frequent in anti–U3 RNP–positive patients (25% versus 14%; P = 0.002), as was “intrinsic” pulmonary arterial hypertension (PAH) (31% versus 13%; P < 0.001). The frequency of gastrointestinal involvement, cardiac involvement, pulmonary fibrosis, and “renal crisis” did not differ significantly between the 2 groups. Survival was worse in the anti–U3 RNP–positive group (hazard ratio 1.38 [95% confidence interval 1.05–1.82]). PAH was the most common known cause of death in patients with anti–U3 RNP (30%, versus 10% in the anti–U3 RNP–negative group; P < 0.001). Conclusion The present findings demonstrate that the frequencies of African American race and male sex are greater among SSc patients with anti–U3 RNP antibody than those without, and the former group is younger at SSc diagnosis. Anti–U3 RNP–positive patients have more frequent skeletal muscle involvement and PAH, the latter being the most common cause of death.
To describe a series of systemic sclerosis (SSc) patients with the unusual combination of scleroderma renal crisis (SRC) and pulmonary hypertension (PHT) without interstitial lung disease.The medical records of 2,459 SSc patients in the University of Pittsburgh Scleroderma Databank first evaluated between 1972 and 1999 were reviewed.Eleven patients (0.45%) had both SRC and PHT. All had been evaluated since 1979, when angiotensin-converting enzyme (ACE) inhibitor therapy for SRC became available. Seven had SSc with limited cutaneous involvement, and 4 had SSc with diffuse cutaneous involvement. SRC occurred first in all patients except 1, in whom the onsets of SRC and PHT were simultaneous. SRC preceded PHT by a mean of 4.3 years. Four patients had anti-Th/To antibody, 5 had anti-RNA polymerase III antibody, 2 had anti-U3 RNP antibody, and none had anticentromere or antitopoisomerase I antibody. Ten of the 11 patients died, 8 from PHT. Ten patients were being treated with ACE inhibitor drugs when PHT developed.In SSc, SRC and PHT are not mutually exclusive complications. SSc patients surviving SRC who have serum antibodies to Th/To, RNA polymerase III, or U3 RNP are at increased risk to develop PHT. ACE inhibitor therapy did not prevent the development of PHT.
Abstract Objective To compare anti‐Th/To–positive and anticentromere antibody (ACA)–positive patients with limited cutaneous systemic sclerosis (lcSSc). Methods We reviewed the medical records of 107 anti‐Th/To–positive patients and 365 ACA‐positive patients who were first evaluated during 1985–2000. ACA was detected by indirect immunofluorescence on HEp‐2 cell substrate, and anti‐Th/To was detected by RNA immunoprecipitation with K562 cell extracts. Patients were included if they had a clinical diagnosis of lcSSc, and excluded if they had >1 SSc‐associated serum autoantibody. Results The final study groups comprised 87 lcSSc patients with anti‐Th/To antibodies and 306 with ACAs. Anti‐Th/To–positive patients were younger ( P < 0.04) and had a shorter disease duration at their first evaluation ( P < 0.003). Patients with anti‐Th/To antibodies had more subtle skin changes, less severe vascular involvement, and less frequent distal esophageal hypomotility. Both groups had a higher frequency of “intrinsic” pulmonary hypertension than has been previously reported in the literature (28% and 19% of anti‐Th/To–positive and ACA‐positive patients, respectively), perhaps due to referral bias. Patients in the anti‐Th/To group more often had radiographic evidence of interstitial lung disease (48% versus 13% of the ACA group; P < 0.0001). Scleroderma renal crisis was uncommon (4 cases), but occurred exclusively in the anti‐Th/To group. Survival among the anti‐Th/To–positive patients was reduced compared with that in the ACA group ( P < 0.02). Conclusion Patients with anti‐Th/To and those with ACA most often develop lcSSc and have a high frequency of “intrinsic” pulmonary hypertension. Compared with the ACA patients, anti‐Th/To lcSSc patients have more subtle cutaneous, vascular, and gastrointestinal involvement, but more often have certain features typically seen in diffuse scleroderma, such as pulmonary fibrosis and scleroderma renal crisis, as well as reduced survival.
Palpable tendon friction rubs (TFRs) in systemic sclerosis (SSc; scleroderma) have been associated with diffuse skin thickening, increased disability, and poor survival. Our objective was to quantify the prognostic implications of palpable TFRs on the development of disease complications and longer-term mortality in an incident cohort of early diffuse cutaneous SSc (dcSSc) patients.We identified early dcSSc patients (disease duration <2 years from the first SSc symptom) first evaluated at the University of Pittsburgh Scleroderma Center between 1980 and 2006 and found to have palpable TFRs. These patients were matched 1:1 with the next consecutive early dcSSc patient without TFRs as a control. All had ≥2 clinic visits and 5 years of followup from the first visit.A total of 287 early dcSSc patients with TFR were identified and matched to 287 controls. The median disease duration was 0.83 years in TFR patients and 1.04 years in controls. The median followup was 10.1 years in TFR patients and 7.9 years in controls. Over the course of their illness, patients with TFRs had a >2-fold risk of developing renal crisis and cardiac and gastrointestinal disease complications, even after adjustment for other known risk factors. Patients with TFRs had poorer 5- and 10-year survival rates.Patients with early dcSSc having ≥1 TFRs are at an increased risk of developing renal, cardiac, and gastrointestinal involvement before and after their first Scleroderma Center visit and have reduced survival. Patients presenting with TFRs should be carefully monitored for serious internal organ involvement.
To determine the long-term outcome and associated clinical, serologic, and pathologic features in a cohort of patients with connective tissue disease (CTD) and the anti-signal recognition particle (anti-SRP) autoantibody.Sera and clinical data were collected prospectively from consecutive adult patients with polymyositis (PM; n = 134), dermatomyositis (n = 129), or other CTDs (predominantly systemic sclerosis [SSc; n = 790]). Patients were first evaluated during 1973-2001.Nineteen patients with the anti-SRP autoantibody were identified, 16 (84%) of whom had pure PM and 3 (2 with SSc and 1 with antisynthetase syndrome) had yet to develop features of myositis after a mean followup of 4.5 years (range 2.5-6 years). More SRP-positive PM patients had severe proximal muscle weakness (50%) and muscle atrophy (67%) at initial presentation compared with antisynthetase-positive PM controls. Cardiac involvement occurred in only 2 of 16 SRP-positive PM patients (13%), and interstitial lung disease was noted in 3 of 13 SRP-positive PM patients (23%) and in the 3 SRP-positive nonmyositis patients. There was a relative lack of inflammation in muscle biopsy specimens from the SRP-positive PM cohort. Other autoantibodies in the SRP-positive patients included Ro/SSA (4 patients), Th/To (1 patient), and anti-PL-12 (1 patient). Survival in the SRP-positive PM patients was comparable with that seen in the cohort of SRP-negative PM patients.The anti-SRP autoantibody is not specific for PM. Severe muscle weakness and atrophy were prominent features in PM patients with anti-SRP. Cardiac involvement was less common and survival was better in patients with anti-SRP than has previously been reported.
Pulmonary arterial hypertension (PAH) and severe pulmonary fibrosis (SPF) are the most common causes of death in scleroderma. Our study focuses on lung disease in patients with a nucleolar antibody in comparison to other scleroderma-specific autoantibodies.Patients initially seen between 1972 and 1995 (and followed through 2004) with [systolic pulmonary artery pressure (sPAH) (PASP > 50 mm Hg] or SPF [forced vital capacity (FVC%) < 55% predicted) were grouped by the presence of anticentromere antibody (ACA), an isolated antinucleolar antibody (ANoA), or an antitopoisomerase antibody-I (TOPO).Twenty percent of ACA, 23% of TOPO, and 32% of ANoA patients had severe lung disease (p < 0.005). In ANoA patients with PAH without severe fibrosis, the FVC was lower (71% predicted) than in ACA patients, suggesting they had some interstitial fibrosis. However, they had a higher FVC%/diffusing capacity for carbon monoxide (DLCO)% ratio than the ACA patients (2.4 vs 1.8). pulmonary hypertension in TOPO patients was associated with a lower FVC%/DLCO% ratio and lower levels of PAP than either the PAH in ACA or ANoA patients.Scleroderma-specific autoantibodies are associated with characteristic subgroups of lung disease. The ANoA patients have a unique mixture of PAH and SPF subgroups of lung disease. Scleroderma-specific autoantibodies and the FVC%/DLCO% ratio are helpful in determining whether a patient has PAH alone, PAH along with pulmonary fibrosis, or secondary PAH from chronic hypoxia with SPF.
Background: Drug hypersensitivity syndromes have been attributed to naive T cell responses to neoantigen generated by the drug. However, the occurrence of patch test confirmed abacavir hypersensitivity syndrome (ABC HSR) within 2 days of first drug exposure, and consistent, robust expansion of ABC-responsive CD8+ T cells in HLA-B*5701+ ABC-unexposed healthy donor peripheral blood mononuclear cells (PBMC) suggest a cross-reacting preexisting HLA-B*5701 restricted memory CD8+ T cell response.
Methods: Memory T cell responses to ABC were examined in 3 ABC-unexposed HLA-B*5701+ healthy donor PBMC exposed to C1R.B57 antigen–presenting cells, which had been cultured overnight ±10 μg/mL ABC and then washed, at a ratio of 10:1 PBMC:APC, in culture for 2 hours. Cells were labelled on ice with interferon-g (IFN-γ) capture reagent (Miltenyi Biotec), warmed and chased for a further 4 hours. IFN-γ+ T cells were detected by surface labelling for CD8, CD4, and IFN-γ-PE and either examined directly by flow cytometry or further concentrated using anti-PE magnetic beads followed by flow cytometry. Next, CD45RAmid-low, CD62Lhi-low CD4+, and CD8+ T cells or CD8+ T cells alone were obtained from three HLA-B*5701+ and 2 HLA-B*5701– donors, representing a sample of the donor’s memory T cells. Sorted memory T cells responded to CEF peptides by secreting IFN-γ in contrast to CD45RAhi, CD62Lhi sorted naive T cells from the same individuals; 5 to 8 x 104 memory CD4+ and CD8+ T cells or memory CD8+ T cells alone were co-cultured with irradiated, ±ABC-treated, C1R.B57 cells for 10 days before re-stimulation with ABC treated and washed C1R.B57 cells.
Results: PBMC from HLA-B*5701+ ABC-naive donors were stimulated for 6 h by ABC-treated C1R.B57 antigen–presenting cells: 2/3 showed a clear ABC-specific CD8+ T cell response above control background. Sorted CD4+ and CD8+ memory T cells cultured in the presence of APC+ABC resulted in the detection of ABC-specific CD8+ T cells in all 3 HLA-B*5701+ donors, but not in 2 HLA-B*5701– donors. ABC-specific CD8+ T cells were also detected from similarly treated, sorted HLA-B*5701+ CD8+ memory T cells.
Conclusions: ABC-reactive HLA-B*5701 restricted memory CD8+ T cells can be detected in ABC-unexposed individuals and can be further expanded ex vivo from the memory CD8+ T cell pool. This suggests that an HLA-B*5701-restricted, memory CD8+ T cell response to a prevalent pathogen cross reacts with the neoantigen generated by ABC.
'/%3e%3c/defs%3e%3cpath fill='%23012169' d='M0 0h10080v5040H0z'/%3e%3cpath stroke='%23fff' stroke-width='.6' d='m0 0 6 3m0-3L0 3' clip-path='url(%23b)' transform='scale(840)'/%3e%3cpath stroke='%23e4002b' stroke-width='.4' d='m0 0 6 3m0-3L0 3' clip-path='url(%23c)' transform='scale(840)'/%3e%3cpath stroke='%23fff' stroke-width='840' d='M2520 0v2520M0 1260h5040'/%3e%3cpath stroke='%23e4002b' stroke-width='504' d='M2520 0v2520M0 1260h5040'/%3e%3cg fill='%23fff'%3e%3cuse xlink:href='%23d' x='2520' y='3780'/%3e%3cuse xlink:href='%23a' x='7560' y='4200'/%3e%3cuse xlink:href='%23a' x='6300' y='2205'/%3e%3cuse xlink:href='%23a' x='7560' y='840'/%3e%3cuse xlink:href='%23a' x='8680' y='1869'/%3e%3cuse xlink:href='%23e' x='8064' y='2730'/%3e%3c/g%3e%3c/svg%3e)