Alan N. Baer

American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort.

We propose new classification criteria for Sjögrens syndrome (SS), which are needed considering the emergence of biologic agents as potential treatments and their associated comorbidity. These criteria target individuals with signs/symptoms suggestive of SS.

Hypocomplementemic urticarial vasculitis syndrome: Clinical and serologic findings in 18 patients

We identify and describe clinical findings in hypocomplementemic urticarial vasculitis syndrome (HUVS), an uncommon to rare illness related to systemic lupus erythematosus (SLE). A patient with recurrent, idiopathic urticaria-like lesions was diagnosed as having HUVS if a lesional biopsy showed leukocytoclastic vasculitis, the serum C1q was markedly decreased, and antibody to C1q was detected in the patients serum. The clinical characteristics, serologic findings, and outcome of patients who met these criteria were determined from prospective and retrospective data, including hospital and office records, patient interviews, previously banked serum samples, and freshly drawn sera. Eighteen patients with HUVS were identified, and high incidences of angioedema, ocular inflammation, glomerulonephritis, and obstructive pulmonary disease were found. Renal and lung biopsies showed mesangial or membranoproliferative glomerulonephritis and severe pulmonary emphysema without vasculitis. Pulmonary function was measured in 17 patients, 11 of whom had dyspnea. All dyspneic patients had moderate to severe airflow obstruction, which progressed in all 11 and subsequently improved in only 1. Six of these 11 patients died of respiratory failure, 1 underwent lung transplantation, and 3 of the remaining 4 have moderately severe to life-threatening respiratory insufficiency. Treatment did not appear to alter the progression of obstructive lung disease. In contrast, renal insufficiency improved with treatment in 2 of 2 patients. Angioedema, ocular inflammation, obstructive lung disease, and glomerulonephritis appear to be common in HUVS, and lung disease causes substantial morbidity and mortality. The pathogenesis of HUVS may involve humoral autoimmunity, although it is not clear how autoimmunity would participate in development of obstructive lung disease. Cigarette smoking appears to be a risk factor for fatal lung disease in HUVS. All patients with HUVS should be made aware of this possibility and should be advised, encouraged, and helped to avoid tobacco smoke.

The pathogenesis of anemia in rheumatoid arthritis: A clinical and laboratory analysis☆

Principal concepts concerning the anemia of RA are summarized in Tables 7 and 8. These concepts have been validated by our analysis of 93 anemic RA patients and by our review of the literature. The fact that anemia in RA may have one or more etiologies, occasionally in the same patient, mandates a reasoned approach to the analysis of anemia in every RA patient in whom it may occur. In particular, iron deficiency is common and determination of bone marrow iron content via an aspirate may be required for a definitive diagnosis. In those RA patients with anemia of chronic disease, the best therapy remains control of the underlying disease, most commonly with second line drugs and/or corticosteroids. The place for recombinant erythropoietin in the therapy of this anemia has not been defined; one specific role for erythropoietin may be in the preparation of RA patients for elective surgery, particularly hip arthroplasty, where correction of the anemia may either obviate the need for transfusion or may allow for donation of blood for purposes of autologous transfusion perioperatively. The pathogenesis of the anemia of chronic disease, as seen in RA anemia, is not completely understood. Inflammatory mediators, particularly the cytokines, appear to be important factors in the impairment of erythropoiesis. The mechanism by which these cytokines impair erythroid progenitor growth and hemoglobin production in developing erythrocytes is an important area for future study.

Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab

Objectives Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs. Methods We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours. Results We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis. Conclusions As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.

Primary Sjögren’s Syndrome as a systemic disease: a study of participants enrolled in an international Sjögren’s Syndrome registry

To study the prevalence of extraglandular manifestations in primary Sjögrens syndrome (SS) among participants enrolled in the Sjögrens International Collaborative Clinical Alliance (SICCA) Registry.

Malignancy in Myositis

Dermatomyositis is associated with an underlying malignancy in about 24% of cases. This association is also true for polymyositis but is less prominent. The malignancy is usually an adenocarcinoma of the ovary, lung, or gastrointestinal tract in Western countries and nasopharyngeal carcinoma in Southeast Asia, Southern China, and Northern Africa. Factors predictive of malignancy in myositis patients include more severe skin and muscle disease and the absence of overlap connective tissue disease features, such as interstitial lung disease. Anti-p155/140 antibodies have a strong predictive value for malignancy in adult patients. Patients with dermatomyositis or polymyositis require an evaluation for occult malignancy at the time of diagnosis and, in some cases, in the event of a subsequent recurrence. This paraneoplastic phenomenon may stem from an immune reaction to antigens expressed in both cancer cells and regenerating fibers in affected muscle.

Myotoxicity associated with lipid-lowering drugs

Purpose of reviewLipid-lowering drugs are associated with myotoxicity, which ranges in severity from myalgias to rhabdomyolysis resulting in renal failure and death. Although rhabdomyolysis is rare, muscle symptoms and serum creatine kinase elevations are sufficiently frequent during the course of lipid-lowering drug therapy to pose diagnostic challenges for the clinician. Progress in our understanding of this form of myotoxicity is reviewed. Recent findingsMuscle pain and weakness are the cardinal symptoms and often interfere with vigorous exercise. These symptoms may occur with or without serum creatine kinase elevations. The risk of myotoxicity is increased by combination statin–fibrate therapy as well as by factors that elevate tissue levels of the lipid-lowering drug, including the dose, drug–drug interactions, and host factors. Underlying neuromuscular diseases may become clinically apparent during statin therapy and may predispose to myotoxicity. The pathophysiology of myotoxicity most probably involves metabolic effects of the statins on the isoprenoid pool and on mitochondrial function. SummaryManagement of myotoxicity requires an evaluation of risk factors prior to prescribing lipid-lowering drugs, attention to muscle symptoms, and withdrawal of drug in the event of significant abnormalities.

Lupus and pregnancy

Systemic lupus erythematosus (SLE) disproportionately affects women in their reproductive age years. Pregnancy in this systemic autoimmune disease has long been associated with poor obstetric outcomes. However, the frequency of pregnancy loss in lupus has dropped to a level commensurate with that of the general US population. The outcomes of lupus pregnancies are better if conception is delayed until the disease has been inactive for at least 6 months, and the medication regimen has been adjusted in advance. Pregnancy in lupus is prone to complications, including flares of disease activity during pregnancy or in the postpartum period, preeclampsia, miscarriage, stillbirth, intrauterine growth retardation, and preterm birth. Active lupus nephritis poses the greatest risk. The recognition of a lupus flare during pregnancy may be difficult because the signs and symptoms may mimic those of normal pregnancy. Monitoring should include baseline and monthly laboratory tests, serial ultrasonography, fetal surveillance tests, and fetal m-mode echocardiography for mothers with SS-A (Ro) or SS-B (La) antibodies. In the absence of any signs or symptoms of active SLE, affected patients require no specific treatment during pregnancy. If hydroxychloroquine was in use before conception, it should be maintained throughout pregnancy. If a woman with SLE has antiphospholipid antibodies, prophylactic treatment with aspirin and/or low-molecular weight heparin is indicated to prevent fetal loss. Lupus flares during pregnancy are generally treated with hydroxychloroquine, low-dose prednisone, pulse intravenous methylprednisolone, and azathioprine. High-dose prednisone and cyclophosphamide are reserved for severe lupus complications but are associated with significant pregnancy-related complications and poor obstetrical outcomes.Systemic lupus erythematosus (SLE) disproportionately affects women in their reproductive age years. Pregnancy in this systemic autoimmune disease has long been associated with poor obstetric outcomes. However, the frequency of pregnancy loss in lupus has dropped to a level commensurate with that of the general US population. The outcomes of lupus pregnancies are better if conception is delayed until the disease has been inactive for at least 6 months, and the medication regimen has been adjusted in advance. Pregnancy in lupus is prone to complications, including flares of disease activity during pregnancy or in the postpartum period, preeclampsia, miscarriage, stillbirth, intrauterine growth retardation, and preterm birth. Active lupus nephritis poses the greatest risk. The recognition of a lupus flare during pregnancy may be difficult because the signs and symptoms may mimic those of normal pregnancy. Monitoring should include baseline and monthly laboratory tests, serial ultrasonography, fetal surveillance tests, and fetal m-mode echocardiography for mothers with SS-A (Ro) or SS-B (La) antibodies. In the absence of any signs or symptoms of active SLE, affected patients require no specific treatment during pregnancy. If hydroxychloroquine was in use before conception, it should be maintained throughout pregnancy. If a woman with SLE has antiphospholipid antibodies, prophylactic treatment with aspirin and/or low-molecular weight heparin is indicated to prevent fetal loss. Lupus flares during pregnancy are generally treated with hydroxychloroquine, low-dose prednisone, pulse intravenous methylprednisolone, and azathioprine. High-dose prednisone and cyclophosphamide are reserved for severe lupus complications but are associated with significant pregnancy-related complications and poor obstetrical outcomes. Target Audience: Obstetricians and Gynecologists and Family Physicians Learning Objectives: After completing the CME activity, physicians should be better able to provide preconception counseling to a woman with lupus, differentiate signs of a lupus flare from symptoms of pregnancy, differentiate preeclampsia from a flare of lupus nephritis, and differentiate the serious medical complications of pregnancy in a lupus patient.

Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases

Elucidating the molecular pathways active in pathologic tissues has important implications for defining disease subsets, selecting therapy, and monitoring disease activity. The development of therapeutics directed at IFN-α or IFN-γ makes the discovery of probes that report precisely on the activity of different IFN pathways a high priority. We show that, although type I and II IFNs induce the expression of a largely overlapping group of molecules, precise probes of IFN-γ activity can be defined. Used in combination, these probes show prominent IFN-γ effects in Sjögren syndrome (SS) tissues. In contrast, dermatomyositis muscle shows a dominant type I IFN pattern. Interestingly, heterogeneity of IFN signatures exists in patients with SS, with some patients demonstrating a predominant type I pattern. The biochemical patterns largely distinguish the target tissues in patients with SS from those with dermatomyositis and provide a relative weighting of the effects of distinct IFN pathways in specific biopsies. In SS, type I and II IFN effects are localized to the same epithelial cells, surrounded by inflammatory cells expressing IFN-γ–induced proteins, suggesting reinforcing interactions. Precise probes of the different IFN pathways active in tissues of complex rheumatic diseases will be critical to classify disease, elucidate pathogenesis, and select therapy.

Flares of systemic lupus erythematosus during pregnancy and the puerperium: prevention, diagnosis and management

Systemic lupus erythematosus is a systemic autoimmune disease that primarily affects women in their reproductive age years. Pregnancy in systemic lupus erythematosus now has favorable outcomes for the majority of women. However, flares of disease activity, preeclampsia, fetal loss, intrauterine growth retardation and preterm birth are established risks of such pregnancies. Active lupus nephritis at the time of conception poses the greatest risk for disease flares and poor obstetric outcomes. Patients should delay conception until their lupus has been in remission for at least 6 months. In addition, certain lupus medications are potentially teratogenic and need to be stopped before conception. The signs and symptoms of a lupus flare may mimic those of normal pregnancy, impeding its recognition during pregnancy. Hydroxychloroquine, low-dose prednisone, pulse intravenous methylprednisolone and azathioprine are commonly used to treat lupus flares during pregnancy.