Systemic sclerosis (SSc) is a heterogeneous autoimmune disorder associated with vascular dysfunction and fibrotic changes in the skin, vasculature and internal organs. Although serologic abnormalities are an important diagnostic tool for SSc, little is known about whether autoantibodies precede clinical diagnosis. Here we investigated the presence of autoantibodies before SSc diagnosis and assessed whether certain autoantibodies might associate with the future onset of scleroderma renal crisis (SRC), a potentially fatal complication of the disease. Using the Department of Defense Serum Repository, autoantibodies were analyzed from archived, prospectively collected, longitudinal serum samples from sixteen individuals with SRC (SSc/SRC) and thirty cases of SSc without SRC (SSc/no SRC), matched for age, sex, and race. Seventy five percent (12/16) of the SSc/SRC and 40% (12/30) of the SSc/no SRC were seropositive for at least one autoantibody prior to clinical diagnosis (up to 27.1 years earlier, mean = -7.4 years). Although both disease groups demonstrated a heterogeneous immunoreactivity profile against the autoantigen panel, the SSc/SRC subjects showed two enriched clusters with one featuring elevated levels of autoantibodies against Ro52 and/or Ro60 and another with high levels of immunoreactivity against the RNA polymerase complex. Consistent with larger spectrum of immunoreactivity and the elevated levels of autoantibodies in SSc/SRC, the total response against the autoantigen panel from the last time point of the seropositive subjects revealed that the SSc/SRC cohort harbored higher antibody levels (p = 0.02) compared to SSc/no SRC. Overall, our findings demonstrate that relevant seropositive autoantibodies often precede the clinical diagnosis of SSc/no SRC and SSc/SRC.

In this SSc cohort, we present a panel of risk factors for future SRC. These patients may benefit from close observation of blood pressure, proteinuria, and estimated glomerular filtration rate, for earlier SRC identification and intervention. Future prospective therapeutic studies could focus specifically on this high-risk population.

Background Scleroderma Renal Crisis (SRC) is associated with significant morbidity and mortality. While prednisone is strongly associated with SRC, there are no previous large cohort studies that have evaluated ace inhibitor (ACEi) calcium channel blocker (CCB), angiotensin receptor blocker (ARB), endothelin receptor blocker (ERB), non-steroidal anti-inflammatory drug (NSAID), fluticasone, or mycophenolate mofetil (MMF) use in systemic sclerosis (SSc) and the risk of SRC. Methods In this retrospective cohort study of the entire military electronic medical record between 2005 and 2016, we compared the use of ACEi, ARB, CCB, NSAID, ERB, fluticasone, and MMF after SSc diagnosis for 31 cases who subsequently developed SRC to 322 SSc without SRC disease controls. Results ACEi was associated with an increased risk for SRC adjusted for age, race, and prednisone use [odds ratio (OR) 4.1, 95% confidence interval (CI) 1.6–10.2, P = 0.003]. On stratified analyses, ACEi was only associated with SRC in the presence [OR 5.3, 95% CI 1.1–29.2, p = 0.03], and not the absence of proteinuria. In addition, a doubling of ACEi dose [61% vs. 12%, p < 0.001) and achieving maximum ACEi dose [45% vs. 4%, p < 0.001] after SSc diagnosis was associated with future SRC. CCB, ARB, NSAIDs, ERB, fluticasone, and MMF use were not significantly associated with SRC. Conclusion ACEi use at SSC diagnosis was associated with an increased risk for SRC. Results suggest that it may be a passive marker of known SRC risk factors, such as proteinuria, or evolving disease. SSC patients that require ACEi should be more closely monitored for SRC.

Background. Erythrodermic psoriasis is a rare and severe variant of psoriasis. It is characterized by widespread skin erythema, scaling, pustules, or exfoliation of more than 75% of the body’s surface area. This condition has life-threatening complications to include hemodynamic, metabolic, immunologic, and thermoregulatory disturbances. One metabolic complication, hyperuricemia, occurs from rapid keratinocyte differentiation and infiltration of inflammatory cells into psoriatic lesions. Although renal injury caused by shunting of blood to the skin has been reported, there are no reports of erythrodermic psoriasis causing crystal-induced nephropathy. We present a case of erythrodermic psoriasis and hyperuricemia complicated by uric acid crystal nephropathy. Case Presentation. A 57-year-old male with long-standing psoriatic arthritis presented with diffuse scaling of his skin. He was being treated with adalimumab, leflunomide, and topical clobetasol, but had recently stopped taking his medications. Physical exam revealed yellow scaling covering his entire body with underlying erythema and tenderness without mucosal involvement. Labs were notable for a creatinine of 3.3 mg/dL, with no prior history of renal disease, and uric acid of 12.7 mg/dL. He was admitted to the intensive care unit given >80% of body surface area involvement and acute renal failure. Despite aggressive fluid resuscitation, renal function did not improve, and creatinine peaked at 4.61 mg/dL. Urine microscopy showed diffuse polymorphic uric acid crystals, consistent with uric acid crystal-induced nephropathy. He was started on rasburicase, urinary alkalinization, and fluids. His renal function improved dramatically; urine output, uric acid, and electrolytes normalized. He was discharged on topical clobetasol and leflunomide and started on secukinumab with little to no skin involvement. Conclusion. This case presents the rare complication of crystal-induced nephropathy in a patient with erythrodermic psoriasis. Uric acid crystal nephropathy is well described in diseases with rapid cell turnover such as tumor lysis syndrome. It is thought that rapid keratinocyte differentiation and inflammatory infiltration of psoriatic lesions produced life-threatening electrolyte abnormalities similar to tumor lysis syndrome. Early recognition of this rare complication is critical, and aggressive fluid resuscitation, urine alkalinization, and uric acid lowering agents should be administered immediately.

Background: Focal segmental glomerulosclerosis (FSGS) is a heterogeneic glomerular disease. Risk factors for end- stage kidney disease (ESKD) and impact of immunosuppression treatment (IST) has varied in previously published cohorts. These cohorts were limited by relatively small case numbers, short follow up, lack of racial/ethnic diversity, a mix of adult and pediatric patients, lack of RAAS inhibition, or lack of subgroup analysis of IST. Methods: We compared demographics, clinical characteristics, histopathology and IST to long term renal survival in a large, ethnically diverse, adult cohort of 338 biopsy-proven FSGS cases with long term follow up in the era of RAAS inhibition using data from the United States Department of Defense health care network. Results: Multivariate analysis showed that nephrotic range proteinuria (NRP), estimated glomerular filtration rate <60 ml/min/1.73m2, hypoalbuminemia, interstitial fibrosis and tubular atrophy, and interstitial inflammation at diagnosis as well as the absence of remission were all associated with worse long term renal survival. IgM, C3, and a combination of IgM/C3 immunofluorescence staining were not associated with reduced renal survival. IST was not associated with improved renal survival in the whole cohort, or in a subgroup with NRP. However, IST was associated with better renal survival in a subgroup of FSGS cases with both NRP and hypoalbuminemia and hypoalbuminemia alone. Conclusion: Our study suggests that IST should be reserved for FSGS patients with nephrotic syndrome. It also introduces interstitial inflammation as a potential risk factor for ESKD and does not support the proposed pathogenicity of IgM and complement activation.