Gurtej S. Cheema

Stevens–Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but potentially life threatening, diseases characterized by widespread epidermal necrosis, and are predominantly medication-induced. Unfortunately, though they are often associated with long-term debilitating sequelae, there are currently no efficacious pharmaceutical interventions proven through large clinical trials. It has been well established that the epidermal damage in these diseases is due to keratinocyte apoptosis. Although drug-specific T cells are implicated in this process, our understanding of the immunopathology is far from complete. The scenario suggested by todays literature points towards drug-specific CD8+ cytotoxic T cells utilizing perforin/granzyme B trigger keratinocyte apoptosis. Subsequently, there may be an expansion of apoptosis involving the interaction of either membrane-bound or soluble Fas ligand (sFasL) with its receptor Fas. The cellular source of sFasL remains controversial, with both peripheral lymphocytes and keratinocytes themselves as potential candidates. Cytokines produced by T lymphocytes, macrophages or keratinocytes may participate by activating keratinocytes and enhancing their expression of Fas and FasL, or by promoting the skin recruitment of lymphocytes by upregulating adhesion molecules. A better understanding of the underlying immunological mechanisms is required to identify appropriate therapeutic interventions. Finally, clinicians must remain vigilant about drug hypersensitivity to prevent SJS/TEN.

Lupus nephritis: A critical review

Lupus nephritis remains one of the most severe manifestations of systemic lupus erythematosus associated with considerable morbidity and mortality. A better understanding of the pathogenesis of lupus nephritis is an important step in identifying more targeted and less toxic therapeutic approaches. Substantial research has helped define the pathogenetic mechanisms of renal manifestations and, in particular, the complex role of type I interferons is increasingly recognized; new insights have been gained into the contribution of immune complexes containing endogenous RNA and DNA in triggering the production of type I interferons by dendritic cells via activation of endosomal toll-like receptors. At the same time, there have been considerable advances in the treatment of lupus nephritis. Corticosteroids have long been the cornerstone of therapy, and the addition of cyclophosphamide has contributed to renal function preservation in patients with severe proliferative glomerulonephritis, though at the cost of serious adverse events. More recently, in an effort to minimize drug toxicity and achieve equal effectiveness, other immunosuppressive agents, including mycophenolate mofetil, have been introduced. Herein, we provide a detailed review of the trials that established the equivalency of these agents in the induction and/or maintenance therapy of lupus nephritis, culminating in the recent publication of new treatment guidelines by the American College of Rheumatology. Although newer biologics have been approved and continue to be a focus of research, they have, for the most part, been relatively disappointing compared to the effectiveness of biologics in other autoimmune diseases. Early diagnosis and treatment are essential for renal preservation.

The emergence of progressive multifocal leukoencephalopathy (PML) in rheumatic diseases

Progressive multifocal leukoencephalopathy (PML) is a rare and devastating neurological disease with areas of demyelination in the central nervous system classically associated with profound imunosuppression. PML is caused by reactivation of latent JC virus, leading to the death of myelin-producing oligodendrocytes typically with a rapidly fatal outcome. Once seen primarily in severely immunosuppressed states including lymphoma, solid organ malignancies, and organ transplant recipients, PML became an AIDS-defining illness in the 1980s. PML has now emerged as a catastrophic illness in multiple sclerosis with biologic drug therapy (natalizumab) and reported in rheumatic diseases with and without biologic therapeutic agents. With current and future treatments that suppress and manipulate the immune system, there is risk for severe acute infections and reactivation of latent infections, such as JC virus reactivation leading to PML. It is critical, therefore, to proceed cautiously when immune system modification strategies are being evaluated for fear of unleashing undesirable or even fatal diseases. Fortunately this complication remains a rare event.

The SAPHO Syndrome

OBJECTIVE To review the epidemiology, presentation, diagnosis, treatment, pathogenesis, and genetics of the syndrome known under the acronym of SAPHO for Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis to heighten awareness of this entity. METHODS We conducted a Medline search using SAPHO syndrome, chronic recurrent multifocal osteitis/osteomyelitis, and related terms as keywords and extracted further relevant articles from the retrieved references. RESULTS The SAHPO acronym identifies a syndrome encompassing a variety of osteoarticular disorders that are frequently accompanied by dermatoses characterized by neutrophilic pseudoabscesses, but can also occur in isolation. SAPHO syndrome is rare, although probably underrecognized because its diagnosis may be challenging because of the wide variability in its musculoskeletal and cutaneous manifestations. This is especially true when atypical sites are involved and when specific skin lesions are absent. There are no standardized treatment protocols available. Current treatments are empirical and have the objective of providing relief from the at times debilitating pain associated with SAPHO syndrome. They include nonsteroidal anti-inflammatory drugs and analgesics as first-line agents. Systemic corticosteroids, disease-modifying anti-rheumatic drugs, biologicals targeting tumor necrosis factor alpha and interleukin-1, and bisphosphonates have all been beneficial in some patients, but ineffective in others. This suggests that the pathogenesis of SAPHO syndrome is multifactorial, but this aspect remains poorly explored, although bacteria and immunological dysfunction are hypothesized to play a role. CONCLUSIONS The early recognition, diagnosis, and prompt treatment of SAPHO syndrome can prevent the unnecessary use of long-term antibiotics or invasive procedures, while rapidly alleviating pain in a majority of affected patients.

The epidemiology of transverse myelitis.

Transverse myelitis is a neurological disorder causing acute spinal cord injury as a result of acute inflammation, often associated with para infectious processes and autoimmune disease. The purpose of this article is to review the literature on the geoepidemiology of transverse myelitis and assess its environmental associations. Articles from 1981 to 2009 were reviewed in Pub Med along with potential causes such as autoimmune disease (focusing on systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome (APS), and Sjogrens), infection, vaccination, and intoxication.

Steroid induced osteonecrosis: An analysis of steroid dosing risk.

Abstract Osteonecrosis is a serious condition involving bone destruction that frequently requires surgical treatment to rebuild the joint. While there is an abundance of literature documenting corticosteroid related osteonecrosis, there is no consensus as to the relative risk of osteonecrosis after administration of steroids via parenteral, oral, topical, inhaled and other routes. This risk is an important prognostic indicator because identification and conservative intervention can potentially reduce morbidity associated with aggressive surgical treatment of osteonecrosis. This paper provides insight into establishing guidelines related to the risk of developing osteonecrosis as a result of corticosteroid use. Case studies, retrospective studies and prospective studies in humans on different corticosteroids and varied dosages were assessed. Most cases of osteonecrosis are secondary to systemically administered corticosteroids and/or high dose daily therapy, particularly in patients with underlying comorbidities including connective tissue diseases, hyperlipidemia, or previous trauma. Previous case reports of osteonecrosis related to inhaled or topical use of steroids are complicated by the fact that in the great majority of cases, the patients are also treated with systemic steroids prior to the development of osteonecrosis. Based on the literature, a set of recommendations regarding the risk of osteonecrosis in patients on steroids was formulated.

The Geo-epidemiology of Temporal (Giant Cell) Arteritis

Giant cell arteritis (GCA) is the most common vasculopathy in patients over the age of 50. The majority of data on the geo-epidemiology of GCA is derived from Scandinavia, although there is very good documentation and epidemiological descriptions from studies throughout Europe and North America. There remains, however, a paucity of data on the incidence and prevalence of GCA in North American minority populations, as well as from Africa or Asia. The data that does exist suggests that the incidence of GCA is lower in Hispanic, Asian, and African American populations. It is interesting to note that as the population throughout the world continues to age, we anticipate an increased prevalence of disease based upon increases in annual incidence and improved survival. Considerable research is still needed to identify genetic, environmental, and gender-specific factors that influence not only the etiology, but also the natural history of disease.

Currents Concepts on the Immunopathology of Amyloidosis

Amyloidosis is defined as the extracellular accumulation at systemic or organ-specific level of insoluble low molecular weight protein fibrils manifesting a beta pleated sheet configuration and a characteristic staining pattern. Several different types of proteins may lead to this phenomenon, and amyloidosis is defined by the biochemical nature of the protein in the deposits and further classified according to whether the deposits are localized or systemic, acquired or inherited, and by the resulting clinical phenotype. Amyloidosis includes subtypes such as light chain, associated with serum amyloid A protein, heritable and familial forms, dialysis-related disease, and organ-specific conditions. The pathogenesis and clinical features of these clinical and pathological entities will be critically discussed in this review article.

Revisiting Libman-Sacks Endocarditis: A Historical Review and Update

Libman–Sacks (LS) endocarditis was first described by Libman and Sacks in 1924, and is characterized by sterile, verrucous valvular lesions with a predisposition for the mitral and aortic valves. It is now regarded as both a cardiac manifestation of systemic lupus erythematosus and, in recent years, of the antiphospholipid syndrome (APS). Though typically mild and asymptomatic, LS endocarditis can lead to significant complications, including severe valvular insufficiency requiring surgery, infective endocarditis, and thromboembolic events, such as stroke and transient ischemic events. Improvements in imaging modalities, particularly in echocardiography, have allowed better estimation of the prevalence of the disease, but further investigation is still needed into its pathogenesis, treatment, and association with APS.

Acute rheumatic fever and its consequences: a persistent threat to developing nations in the 21st century.

Acute rheumatic fever (ARF) is an autoimmune, multi-system response secondary to molecular mimicry following Lancefield group A streptococcus (GAS) pharyngitis; it is now most commonly found in the pediatric populations of developing nations. The major source of morbidity and mortality of ARF stems from rheumatic heart disease (RHD), although the cardinal symptoms of the disease also include polyarthritis, Sydenhams chorea, subcutaneous nodules, and erythema marginatum. Therapy is aimed towards treating the initial GAS infection, using anti-inflammatory medications for acute symptoms and surgery to correct RHD. Secondary prevention is crucial, given the high risk of recurrence, and includes long-term antibiotic prophylaxis. However, vaccination towards GAS may soon be on the horizon, which may assist in both decreasing the risk of initial infection in naïve patients and helping to lower the risk of recurrence.