Posted On: May 3, 2014
Different Treatments Of Lupus
There are many segments of treatment of Lupus, like Glucocorticoids, Hydroxychloroquine, Cyclophosphamide, Azathioprine, Mycophenolate mofetil, Calcineurin inhibitors, Rituximab. It depends on the complexity of the chronic illness and the affected body parts.
Let us go through the associated risks of those segments involved in Lupus treatment:
Two categories of toxic effects result from the therapeutic use of corticosteroids:
a) Those resulting from withdrawal of steroid therapy,
b) And those resulting from continued use at supraphysiological doses.
The side effects from both categories are potentially life-threatening and mandate a careful assessment of the risks and benefits in each patient. Let’s check out some of the side effects we come across frequently.
The most frequent problem in steroid withdrawal is the flare-up of the underlying disease for which steroids have been prescribed. There are several other complications associated with steroid withdrawal. The most severe complication of steroid termination, acute adrenal insufficiency, results from exaggeratedly rapid withdrawal of corticosteroids after prolonged therapy has suppressed the HPA axis. The therapeutic approach to acute adrenal insufficiency is detailed below.
There is a significant variation among patients with respect to the degree and duration of adrenal suppression after Glucocorticoid therapy, making it difficult to establish the relative risk in any given patient. Many patients recover from Glucocorticoid-induced HPA suppression within several weeks to months; however, in some individuals, the time for recovery can vary to one year or longer.
In an effort to diminish the risk of the dearth of iatrogenic acute adrenal, protocols for discontinuing corticosteroid therapy in patients receiving long-term treatment with corticosteroids have been proposed, generally without rigorous documentation of their efficacy. Patients who have received supraphysiological doses of Glucocorticoids for a period of 2 to 4 weeks within the preceding year should be considered to have some degree of HPA impairment in settings of acute stress and should be treated accordingly.
In addition to this most severe form of withdrawal, a characteristic Glucocorticoid withdrawal syndrome consists of fever, myalgias, arthralgias, and malaise, which may be difficult to differentiate from some of the underlying diseases for which steroid therapy was instituted. Finally, pseudotumor cerebri, a clinical syndrome that includes increased intracranial pressure with papilledema, is a rare condition that sometimes is associated with reduction or withdrawal of corticosteroid therapy.
Besides the consequences that result from the suppression of the HPA axis, there are a number of other complications that result from prolonged therapy with corticosteroids. These include fluid and electrolyte abnormalities, hypertension, hyperglycemia, increased susceptibility to infection, osteoporosis, myopathy, behavioral disturbances, cataracts, growth arrest, and the characteristic habitues of steroid overdose, including fat redistribution, striae, and ecchymoses.
Alterations in fluid and electrolyte handling can cause hypokalemic alkalosis, edema, and hypertension, particularly in patients with primary hyperaldosteronism secondary to an adrenal adenoma or in patients treated with potent mineralocorticoids. Similarly, hypertension is a relatively common manifestation in patients with endogenous Glucocorticoid excess and can even be seen in patients treated with Glucocorticoids lacking appreciable mineralocorticoid activity.
Side Effects Related to Metabolic Changes
The effects of Glucocorticoids on intermediary metabolism have been described above. Hyperglycemia with glycosuria usually can be managed with diet and/or insulin and its occurrence should not be a major factor in the decision to continue corticosteroid therapy or to initiate therapy in diabetic patients.
Side Effects Related to Immune Responses
Because of their multiple effects to inhibit the immune system and the inflammatory response, Glucocorticoid use is associated with an increased susceptibility to infection and a risk of reactivation of latent tuberculosis. In the presence of known infections of some consequence, Glucocorticoids should be administered only if absolutely necessary and concomitantly with appropriate and effective antimicrobial or anti-fungal therapy.
Other Possible Risk of Peptic Ulcers
There is considerable debate about the association between peptic ulcers and Glucocorticoid therapy. The possible onset of hemorrhage and perforation in these ulcers and their insidious onset make peptic ulcers serious therapeutic problems; there has been several studies estimating the degree of risk from corticosteroids. Most patients who develop gastrointestinal bleeding while receiving corticosteroids also received nonsteroidal anti-inflammatory agents, which are known to promote ulceration, such that the pathogenic role of corticosteroids remains open to debate. Nonetheless, it is prudent to be especially vigilant for peptic ulcer formation in patients receiving therapy with corticosteroids, especially when administered concomitantly with nonsteroidal anti-inflammatory drugs.
Side Effect of Corticosteroids Causing Myopathy
Myopathy characterized by weakness of proximal limb muscles, can occur in patients taking large doses of corticosteroids and also is part of the clinical picture in patients with endogenous Cushing’s syndrome. It can be of sufficient severity to impair ambulation and is an indication for withdrawal of therapy. Attention also has focused on steroid myopathy of the respiratory muscles in patients with asthma or chronic obstructive pulmonary disease; this complication can diminish respiratory function. Recovery from the steroid myopathies may be slow and incomplete.
Side Effect of Corticosteroids Causing Behavioral Changes
Behavioral disturbances are common after administration of corticosteroids and in patients who have Cushing’s syndrome secondary to endogenous hypercorticism; these disturbances may take many forms, including nervousness, insomnia, changes in mood or psyche, and overt psychosis. Suicidal tendencies are not uncommon. A history of previous psychiatric illness does not preclude the use of steroids in patients for whom they are otherwise indicated. Conversely, the absence of a history of previous psychiatric illness does not guarantee that a given patient will not develop psychiatric disorders while on steroids.
Side Effect of Glucocorticoid Therapy Causing Cataracts
Cataracts are a well-established complication of Glucocorticoid therapy and are related to dosage and duration of therapy. Children appear to be particularly at risk. Cessation of therapy may not lead to complete resolution of opacities, and cataracts may progress despite reduction or cessation of therapy may not lead to complete resolution of opacities, and cataracts may progress despite reduction or cessation of therapy. Patients on long-term Glucocorticoid therapy at doses of prednisone of 10 to 15 mg/day or greater should receive periodic slit-lamp examinations to detect Glucocorticoid-induced posterior subcapsular cataracts.
Side Effect of Glucocorticoid Therapy Causing Osteoporosis
Osteoporosis, a frequent serious complication of Glucocorticoid therapy, occurs in patients of all ages and is related to dosage and duration of therapy. A reasonable estimate is that 30% to 50% of all patients who receive chronic Glucocorticoid therapy ultimately will develop osteoporotic fractures. Glucocorticoids preferentially affect trabecular bone and the cortical rim of the vertebral bodies; the ribs and vertebrae are the most frequent sites of fracture. Glucocorticoids decrease bone density by multiple mechanisms, including inhibition of gonadal steroid hormones, diminished gastrointestinal absorption of Ca2+, and inhibition of bone formation due to suppressive effects on osteoblasts and stimulation of resorption due to effects on osteoclasts mediated by changes in the production of osteoprotegerin and RANK ligand. In addition, Glucocorticoid inhibition of intestinal Ca2+ uptake may lead to secondary increases in parathyroid hormone, thereby increasing bone desorption.
The considerable morbidity of Glucocorticoid-related osteoporosis has led to efforts to identify patients at risk for fractures and to prevent or reverse bone loss in patients requiring chronic Glucocorticoid therapy. The initiation of Glucocorticoid therapy is considered an indication for bone densitometry, preferably with techniques such as dual-energy x-ray absorptiometry of the lumbar spine and hip that detects most sensitive abnormalities in trabecular bone. Because bone loss associated with Glucocorticoids predominantly occurs within the first 6 months of therapy, densitometric evaluation, and prophylactic measures should be initiated with therapy or shortly thereafter. Most authorities advocate maintaining a Ca2+ intake of 1500 mg/day by diet plus Ca2+ supplementation and vitamin D intake of 400 IU/day, assuming that these measures do not increase urinary calcium excretion above the normal range. Although gonadal hormone replacement therapy has been widely used in specific groups of patients receiving chronic Glucocorticoid therapy, this is the subject of considerable debate based on recently published results from randomized, placebo-controlled trials. Recombinant parathyroid hormone recently has received considerable attention as a potential therapy of Glucocorticoid-induced osteoporosis.
The most important advance to date in the prevention of Glucocorticoid-related osteoporosis is the successful use of bisphosphonates, which have been shown to decrease the decline in bone density and the incidence of fractures in patients receiving Glucocorticoid therapy.
Side Effect of Glucocorticoid Therapy Causing Osteonecrosis
Osteonecrosis (also known as avascular or aseptic necrosis) is a relatively common complication of Glucocorticoid therapy. The femoral head is affected most frequently, but this process also may affect the humeral head and distal femur. Joint pain and stiffness usually are the earliest symptoms, and this diagnosis should be considered in patients receiving Glucocorticoids who abruptly develop hip, shoulder, or knee pain. Although the risk increases with the duration and dose of Glucocorticoid therapy, Osteonecrosis also can occur when high doses of Glucocorticoids are given for short periods of time. Osteonecrosis generally progresses, and most affected patients ultimately require joint replacement.
Side Effect of Glucocorticoid Therapy Causing Encumbrance of Growth and Development
Growth retardation in children can result from administration of relatively small doses of Glucocorticoids. Although the precise mechanism is unknown, there are reports that collagen synthesis and linear growth in these children can be restored by treatment with growth hormone; further studies are needed to define the role of concurrent treatment with growth hormone in this setting. Further studies also are needed to explore the possible effects of exposure to corticosteroids in utero. Studies in experimental animals have shown that antenatal exposure to Glucocorticoids is clearly linked to cleft palate and altered neuronal development, ultimately resulting in complex behavioral abnormalities. Although the actions of Glucocorticoids promoting cellular differentiation play an important physiological role in human development in the neonatal period (e.g., induction of the hepatic gluconeogenic enzymes and surfactant production in the lung) the possibility remains that antenatal steroids can lead to subtle abnormalities in fetal development.
High daily doses of hydroxychloroquine (>250 mg) can result in irreversible retinopathy and ototoxicity. Retinopathy presumably is related to drug accumulation in melanin-containing tissues and can be avoided if the daily dose is 250 mg (Rennie, 1993). Prolonged therapy with high doses of hydroxychloroquine can also cause toxic myopathy, cardiopathy, and peripheral neuropathy. These reactions improve if the drug is withdrawn promptly (Estes et al., 1987). Rarely, neuropsychiatric disturbances, including suicide, may be related to overdose
- Bone marrow toxicity.
- Mucosal ulceration.
- Nephrotoxicity and hemorrhagic cystitis [can be prevented by coadministration of 2-mercaptoethanesulfonate (mesna or MESNEX)].
- Pulmonary fibrosis.
- Permanent amenorrhea, particularly in perimenopausal women and sterility, and an irreversible azoospermia in men.
The major side effect of azathioprine is bone marrow suppression, including leukopenia (common), thrombocytopenia (less common), and/or anemia (uncommon). Other important adverse effects include increased susceptibility to infections (especially varicella and herpes simplex viruses), hepatotoxicity, alopecia, GI toxicity, pancreatitis, and increased risk of neoplasia.
V. Mycophenolate mofetil
The principal toxicities of mycophenolate mofetil are gastrointestinal and hematologic . These include leukopenia, diarrhea, and vomiting. There also is an increased incidence of some infections, especially sepsis associated with cytomegalovirus. Tacrolimus in combination with mycophenolate mofetil has been associated with devastating viral infections including polyoma nephritis.
VI. Calcineurin inhibitors
The principal adverse reactions to cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, hyperlipidemia, and gum hyperplasia. Hyperuricemia may lead to worsening of gout, increased P-glycoprotein activity, and hypercholesterolemia. Nephrotoxicity occurs in the majority of patients treated and is the major indication for cessation or modification of therapy. Hypertension occurs in approximately 50% of renal transplant and almost all cardiac transplant patients. Combined use of calcineurin inhibitors and Glucocorticoids is particularly diabetogenic, although this apparently is more problematic in patients treated with tacrolimus (see below). Especially at risk are obese patients, African-American or Hispanic recipients, or those with a family history of type II diabetes or obesity. Cyclosporine, as opposed to tacrolimus, is more likely to produce elevations in LDL cholesterol.
Nephrotoxicity, neurotoxicity (tremor, headache, motor disturbances, seizures), GI complaints, hypertension, hyperkalemia, hyperglycemia, and diabetes are all associated with tacrolimus use. As with cyclosporine, nephrotoxicity is limiting. Tacrolimus has a negative effect on pancreatic islet beta cells, and glucose intolerance and diabetes mellitus are well-recognized complications of tacrolimus-based immunosuppression. As with other immunosuppressive agents, there is an increased risk of secondary tumors and opportunistic infections. Notably, tacrolimus does not adversely affect uric acid or LDL cholesterol.
Rituximab infusional reactions can be life-threatening, but with pretreatment are usually mild and limited to fever, chills, throat itching, urticaria, and mild hypotension. All respond to decreased infusion rates and antihistamines. Uncommonly, patients may develop severe mucocutaneous skin reactions, including Stevens-Johnson syndrome. Rituximab may cause reactivation of hepatitis B virus or rarely, JC virus (with progressive multifocal leukoencephalopathy). Patients should be screened for hepatitis B before initiation of therapy. Hypogammaglobulinemia and autoimmune syndromes (idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia, pure red cell aplasia, and delayed neutropenia) may supervene 1-5 months after administration.
I suppose you are finding this comprehensive study of the side-effects of different Lupus treatments a bit strongly medically-termed. And, thus looks very scary to you. But, this isn’t to scare you off. With a healthy lifestyle, you can control the side-effects and even give a hard fight to “Lupus”.
Be Healthy Be Strong, Give Lupus A Hard Fight. 🙂