Drug-induced rheumatic syndromes Anupam Wakhlu, Rasmi Ranjan Sahoo, Durga Prasanna Misra Indian Journal of Rheumatology 2019 14(5):1-2

Drug-induced vasculitis Durga Prasanna Misra, Pallavi Patro, Aman Sharma Indian Journal of Rheumatology 2019 14(5):3-9 Vascular injury due to drugs is recognized as a distinct entity under the Chapel Hill Consensus Conference 2012 definitions for vasculitis. Drug-induced vasculitis (DIV) may affect various types of vessels. Isolated cutaneous leukocytoclastic vasculitis is most commonly seen in association with antibiotics and nonsteroidal anti-inflammatory drugs. Drug-induced antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis has been classically associated with cocaine (alone or contaminated with levamisole), antithyroid drugs (propylthiouracil, methimazole, carbimazole) and hydralazine; minocycline often mimics medium-vessel vasculitis, with ANCA positivity. Drug-induced large-vessel vasculitis remains rare; however, it has been reported with anticancer agents targeting immune pathways, including immune checkpoint inhibitors. Cerebral vasculitis has been associated with oral or topical sympathomimetic drug use. Operational pathogenetic mechanisms in DIV include immune complex deposition, abnormal generation of neutrophil extracellular traps, and bypassing of normal immune checkpoints like that between programmed cell death ligand 1 on dendritic cells and programmed cell death 1 on T-lymphocytes. DIV can have an unpredictable course, and a significant proportion of patients require immunosuppressive therapy in addition to drug withdrawal.

Drug-induced lupus Kavadichanda Chengappa G Indian Journal of Rheumatology 2019 14(5):10-18 Drug-induced lupus erythematosus (DILE) is an important differential to consider in a clinical setting of mild lupus. Numerous drugs ranging from the classically described procainamide and hydralazine to novel biological agents such as anti-tumor necrosis factors and immune checkpoint inhibitors are implicated in causing DILE. Various pathophysiologic mechanisms such as decreased central tolerance, molecular cross-reactivity, and epigenetic modifications of immune cells are known to play a role in the precipitation of drug-induced autoimmunity. Early recognition and prompt withdrawal of the offending agent is often sufficient to treat these autoimmune manifestations. A thorough knowledge of DILE is essential to ensure better patient care and better understand the role of xenobiotics in precipitating autoimmunity.

Drug-Induced Interstitial Lung Disease Wei-I Lee, Pravin Hissaria Indian Journal of Rheumatology 2019 14(5):19-26 Drug-induced interstitial lung disease (DIILD) represents a rare but potentially fatal adverse drug reaction. A large number of drugs have been implicated to have this potential risk, including chemotherapeutics and disease-modifying antirheumatic drugs. The clinical presentations, laboratory investigations, pulmonary function test result, and imaging and histopathological findings associated with drug-induced pulmonary fibrosis are nonspecific. The diagnosis is achieved after the exclusion of alternative diagnosis, such as infection, pulmonary edema, and connective tissue diseases. However, sometimes, the underlying diseases (e.g., rheumatoid arthritis) and the drugs used to treat the disease (e.g., methotrexate) can both cause ILD; it is often difficult to tease out causality especially if baseline pulmonary assessment (respiratory function test and imaging) is incomplete prior to the commencement of the drug therapy. Many efforts have been put into investigating the pathogenesis of the DIILD, particularly as animal model of bleomycin-induced pulmonary fibrosis has been used as a surrogate for idiopathic pulmonary fibrosis. However, more research is required to improve our understanding of pathogenesis in order to develop more sensitive and specific diagnostic tests as well as to establish evidence-based treatment approach.

Drug-induced myopathy Manesh Manoj, Rasmi Ranjan Sahoo, Kasturi Hazarika, Prashant Bafna, Anupam Wakhlu Indian Journal of Rheumatology 2019 14(5):27-36 A number of medications, including very commonly used ones, have been described as causing myopathy. Drug-induced myopathy is defined as an acute or subacute adverse effect of a drug on the muscular system, which may range from asymptomatic increase in serum creatine kinase and simple myalgias to life-threatening rhabdomyolysis. It is necessary for the treating physician to recognize these manifestations early and manage promptly; in order to prevent treatment-related morbidity and mortality. A PubMed search was conducted using the MeSH terms “drug AND myopathy” and “drug AND rhabdomyolysis.” The consensus of the authors was sought to finalize a group of 60 articles for further review. With the large number of drugs available to the treating physician today, and the significant drug interactions that can occur, knowledge about the various drugs causing myopathy, their characteristic features if any, and the optimal management of these adverse effects is imperative.

Drug-induced psoriasis Sunil Dogra, Divya Kamat Indian Journal of Rheumatology 2019 14(5):37-43 Psoriasis is known to be triggered by a number of factors including drugs. Some therapeutic agents for the treatment of psoriasis are also known to have a paradoxical effect and alter the course of the disease. The drugs may either cause de novo psoriasis or are responsible for aggravating preexisting psoriasis. The distinction is not always clear-cut and is clinically often indistinguishable from psoriasis vulgaris. The morphological types can vary from plaque psoriasis to pustular psoriasis and even erythroderma. There are certain established agents which are known to trigger psoriasis. Many of the biological agents and targeted therapies available today can trigger psoriasis by activating signaling pathways. The lag time between the intake of drug and onset of psoriasis is highly variable and thus requires a high index of suspicion. Due to the various systemic comorbidities, patients with psoriasis often receive polypharmacy and hence it is important for dermatologists, rheumatologists, and physicians to be aware of the possible triggers.

Drug-induced bone disorders: A systematic review Anshita Aggarwal, Meha Sharma, Indira Maisnam, Soumitra Ghosh, Sameer Aggarwal, Saptarshi Bhattacharya, Deep Dutta Indian Journal of Rheumatology 2019 14(5):44-51 Drug-induced bone disorders are a group of disorders characterized by osteomalacia or osteoporosis, with the common denominator being the iatrogenic nature of the disease. Drug-induced bone disorders are either due to the drug directly effecting the bone microarchitecture (osteoblastic or osteoclastic activity) or indirectly by interfering with Vitamin D metabolism, Vitamin D/calcium absorption, and excess calcium loss or due to altered hormone states which promote bone loss (hypogonadism, hyperthyroidism, somatostatin excess states, insulin deficiency, increased systemic inflammation, and oxidative stress). References for this review were identified through searches of PubMed, Medline, and Embase for articles published until July 2019 using the terms “drug induced bone disorders” (MeSH Terms) AND “osteoporosis” (All Fields) OR “osteomalacia” (All Fields). Anti-epileptics, proton pump inhibitors, glucocorticoids, immunosuppressants (calcineurin inhibitors), anticoagulants, glitazones, SGLT2 inhibitors, somatostatin analogs, anticancer medications, and protein kinase inhibitors are some of the commonly used medications associated with bone mineral loss. An increased awareness, minimizing the use of these medications in patients at increased risk of fractures, keeping dosage and duration of therapy to the lowest, ensuring Vitamin D and calcium adequacy either through diet or supplements, and prophylactic use of bisphosphonates (where indicated) can play a major role in preventing morbidity associated with drug-induced bone disorders.

Drug-induced fibrosing syndromes: A scoping review Sakir Ahmed, Prasanta Padhan, Partisha Gupta Indian Journal of Rheumatology 2019 14(5):52-58 There are numerous case reports implicating drugs in the pathogenesis of scleroderma-like fibrotic syndromes. A MEDLINE and SCOPUS search was made in an attempt to review these drugs. The entire spectrum of sclerodermatous disorders ranging from localized morphea, fasciitis, and linear scleroderma to the classical diffuse systemic sclerosis with typical autoantibody formation have been reported in association with drugs. Some drugs such as bleomycin and pentazocine have been established to cause fibrosis and are used to create animal models of systemic sclerosis. There are controversies regarding the role of others such as beta-blockers. Certain chemotherapeutic agents and ergot derivatives can also lead to fibrosing disorders. The new checkpoint inhibitors have been shown to develop systemic sclerosis like disease among other “immune related adverse effects.” The mechanisms leading to fibrosis are poorly understood in case of most drugs due to paucity of data. This limits therapeutic strategies. However, many of these syndromes regress if the causative drug is withdrawn early. Thus, it is imperative for clinicians to have knowledge about these syndromes and identify them early.

Drug reaction with eosinophilia and systemic symptoms syndrome KC Shanoj, Sneha Joseph, Padmanabha Shenoy Indian Journal of Rheumatology 2019 14(5):59-66 Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a delayed form of severe cutaneous adverse reaction (SCAR) seen in association with certain drugs, especially anticonvulsants and allopurinol. Unlike other SCARs, DRESS is associated with significant systemic involvement such as fever, lymphadenopathy, eosinophilia, renal failure, transaminitis, and myocarditis. Because of delayed onset of symptoms and a persistent course even after discontinuation of culprit drug, DRESS can mimic a variety of rheumatological disorders. Even though glucocorticoids are the mainstay of treatment, unlike other SCARs, DRESS is associated with a high incidence of viral reactivation, especially with members of the human Herpesviridae family. Early identification of the viral activation and prompt therapy is critical in the management of DRESS.

Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum for the rheumatologist Jyoti Ranjan Parida, Saumya Ranjan Tripathy Indian Journal of Rheumatology 2019 14(5):67-75 Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) represent a spectrum of mucocutaneous manifestations characterized by widespread epidermal and/or mucosal detachment from dermis. It occurs due to Type IV hypersensitivity leading to keratinocyte apoptosis. Many extrinsic and intrinsic defects in the apoptotic pathway have been postulated to result in its dysregulation. The characteristic skin lesions of SJS/TEN include ill-defined, coalescing, red macules with necrotic centers followed by extensive epidermal detachment. Mucosa is involved in up to 90% of cases causing erosions and crusts that may precede or follow skin lesions. Supportive care is the mainstay of treatment and if not started promptly may result in high mortality and morbidity. Although many immunosuppressive drugs have been tried in treatment, no treatment has proven beneficial except cyclosporine which has been shown to retard the progression of SJS/TEN. A patient with SJS/TEN as a presenting feature poses two-fold challenge to a rheumatologist as it could be a manifestation of lupus or side effects of a myriad of drugs used by the rheumatologist.