Drugs Used to Manage SLESteroids are a group of chemicals that make up a large portion of the hormones in your body. One of these steroids, cortisone, is a close relative of cortisol, which the adrenal glands in your body make as a natural anti-inflammatory high dose corticosteroids lupus. Synthetic cortisone medications are some of the most effective treatments for reducing the swelling, warmth, pain, and tenderness associated with the inflammation of lupus. Cortisone usually works quickly to relieve these symptoms. However, cortisone can also cause many unwelcome side effects, so it is usually prescribed only when tren marruecos espana medications—specifically NSAIDs and anti-malarials—are not sufficient enough to control lupus. However, it is important to remember that high dose corticosteroids lupus make up a large group of molecules with different functions, high dose corticosteroids lupus the steroids high dose corticosteroids lupus to treat lupus—specifically, corticosteroids—are different than those you may hear about on the news.
Medications - Lupus International
SLE treatment has evolved from the use of conventional drugs such as hydroxychloroquine and corticosteroids, nonspecific immunosuppressants including mycophenolate mofetil, to targeting selective components of the immune cascade with a view to increased efficacy, tolerability and safety profile.
These novel treatments include B-cell-depleting antibodies and fusion proteins that block the costimulatory pathways of B and T cells. A discussion of these pharmacological options and ongoing research forms the basis of this review. The treatment of systemic lupus erythematosus SLE has evolved in the last few decades owing to improved understanding of the inflammatory and immunological processes underpinning the disease. Although many drugs are available for the use in SLE, most are used off-label.
SLE is a complex, heterogeneous autoimmune disease, which involves inflammatory processes in multiple-organ systems resulting in a broad range of clinical phenotypes from mild to severe.
It is a remitting and relapsing disease with substantial patient-to-patient variation in clinical and serological manifestations. The prevalence of SLE is approximately 28—60 per , people [ Johnson et al. The hallmark of the disease is the formation of auto-antibodies resulting in immune complex deposition, complement activation and end-organ failure. Some of the mechanisms behind this cascade include loss of immune tolerance, increased antigenic load, excess T-cell help, defective B-cell suppression and abnormal T-cell immune responses which lead to B-cell hyperactivity and subsequently to the production of pathogenic autoantibodies [ Mok and Lau, ].
Flares can be induced by UV light and infections, so patients should be advised to wear sunblock effective against UVA and UVB at least factor 25 and sun-protective clothing, and to obtain treatment for infections promptly. SLE can be broadly categorized into mild, moderate and severe disease with autoimmune glomerulonephritis being the most common, life-threatening complication.
Other majororgan involvement that can be associated with significant morbidity and mortality include neuropsychiatric, cardiopulmonary and haematological manifestations. Milder disease usually comprises mucocutaneous and musculoskeletal manifestations that can be treated with simpler, less-toxic treatment pathways.
The treatment of moderate to severe disease comprises initially a period of intensive immunosuppressive treatment called induction therapy. The focus of induction therapy is to halt any ongoing systemic inflammation and to induce remission by controlling immunological activity. This is followed by less-aggressive maintenance therapy to consolidate remission and reduce the risk of flares [ Mosca et al.
In some SLE patients, the disease course may be aggressive and unresponsive to established therapies such as corticosteroids, azathioprine and cyclophosphamide. Toxicity associated with prolonged use of these drugs can contribute to increased morbidity and mortality. As a result, there is a continuing need to develop new therapies that can be used in refractory cases and that are less toxic and more effective than standard treatment.
This article reviews traditional therapeutic options for the management of SLE and emerging therapeutic agents. These new treatments have been developed to target various stages in the immune cascade involved in the pathogenesis of SLE, including monoclonal antibody therapy targeted against B- and T-cell molecules. Nonsteroidal anti-inflammatory drugs NSAIDs are commonly used for the symptomatic management of arthralgia, mild arthritis, myalgia, serositis and fever in patients with SLE.
They do not have any immunosuppressive properties. Despite their widespread use in the lupus population there is little trial evidence for safety or efficacy. They should be used for short periods of time and with caution especially in patients with renal involvement, hypertension and established heart disease. They can cause fluid retention, renal impairment and interstitial nephritis. The more cyclo-oxygenase-2 Cox-2 -selective NSAIDs in particular may increase the risk of heart attack and stroke, although they may cause less dyspepsia and peptic ulceration than traditional, less-selective NSAIDs.
Active peptic ulceration and pre-existing renal disease are contraindications to their use [ Lander et al. Antimalarial drugs have been used in rheumatology for the treatment of SLE for many years.
Chloroquine sulphate and phosphate are associated with the greatest risk of ocular toxicity and are now rarely prescribed.
Mepacrine may be useful for lupus-induced skin rashes but it has little effect on other manifestations. Hydroxychloroquine has emerged as the drug of choice and some experts advocate its use in all patients provided that there are no contraindications. Owing to its anti-inflammatory and immunomodulatory properties, it has a significant impact on the long-term outcome by modifying the course of illness through reduction of low-grade flares and hence slows progression to severe disease requiring more intense treatment.
Hydroxychloroquine is most useful in the management of mucocutaneous, musculoskeletal and constitutional symptoms such as fatigue and fever. Recently, hydroxychloroquine has been shown to have cardioprotective properties in several studies, by reducing total cholesterol, low-density lipoprotein LDL cholesterol and triglycerides TG and increasing high-density lipoprotein HDL cholesterol levels [ Petri et al.
Hydroxychloroquine has a good safety profile and toxicity is infrequent, mild and largely reversible. In pregnancy, it is safe with noticeable reduction in SLE activity and no adverse effects on the child [ Buchanan et al.
Retinal toxicity and macular damage are rare with hydroxychloroquine. Owing to the remote risk of hydroxychloroquine-related maculopathy, guidance from the Royal College of Ophthalmology, UK, states that doses should not exceed 6.
Age-related macular degeneration may preclude monitoring for ocular toxicity [ Royal College of Ophthalmologists, The British Society of Rheumatology and British Association of Dermatologists, ]. Mepacrine is used mainly to treat discoid lupus and subacute cutaneous lupus erythematosus. It can be combined with hydroxychloroquine due to the synergistic benefits of antimalarials. There are negligible effects on ocular toxicity; however, mepacrine can cause other side effects such as yellowing of the skin and bodily fluids, which resolves once the drug is discontinued [ D'Cruz, ].
For many decades corticosteroids given in different preparations have been central to the treatment of SLE due to their anti-inflammatory properties in the short term and immunosuppressive actions in the long term. Topical steroids may be used for inflammatory skin rashes and, in severe cases of discoid lupus, intralesional preparations can be used. For localized soft tissue and joint involvement, intra-articular steroid injections with or without local anaesthetic agent may be a more direct and preferred treatment option.
In mild disease, prednisolone is given in doses starting at 0. The dose rises to 0. At such high doses, pulse therapy with intravenous IV methylprednisolone MP; — mg on one to three occasions is deemed by many physicians to be safer with fewer associated side effects. Several studies have shown that a short course of moderate-dose corticosteroids can not only treat active disease but can also help prevent flares in clinically stable but serologically active patients.
In practice, however, physicians usually stop steroid reduction in serologically active patients and await clinical manifestations before increasing doses due to the toxicity of steroids. Corticosteroid treatment is not without complications. Patients are at risk of dose-related immediate problems such as fluid retention, hypertension, blurred vision and infection and more gradual effects such as weight gain, steroid-induced diabetes, osteoporosis and avascular necrosis.
Corticosteroids contribute to premature atherosclerosis as they have pro-atherogenic properties through adverse effects on metabolic factors such as body fat distribution, blood pressure and glucose metabolism [ Barnes et al. Azathioprine is commonly used for the induction of remission and as a steroid-sparing agent in mild-to-moderate disease. It works by affecting cell-mediated and humoral immune responses via the inhibition of lymphocyte proliferation, reduction in antibody production and suppression of natural killer cell activity.
In severe disease, it is used as maintenance therapy and data from lupus nephritis trials show significant improvement in disease activity following induction therapy with cyclophosphamide or mycophenolate mofetil MMF [ Mok et al. It may be associated with gastrointestinal side effects, such as nausea, vomiting and diarrhoea, occasionally severe enough to lead to drug withdrawal.
Mild transaminitis may occur and reversible bone marrow suppression is not uncommon. Unique to azathioprine is the association with genetic polymorphisms that cause decreased thiopurine methyltransferase TPMT activity and thus impaired ability to degrade 6-mercaptopurine into the inactive metabolite.
Cyclophosphamide is an alkylating agent, which causes cell death at any stage of the cell cycle. It also depletes both B and T cells, hence reducing the production of pathogenic auto-antibodies [ Boumpas and Papadimitraki, ]. It may be given orally or intravenously, however, research suggests that intermittent IV pulse therapy has a better efficacy-to-toxicity ratio and hence has largely replaced oral dosage.
Trials conducted by the National Institutes of Health NIH have shown more benefit from IV cyclophosphamide than high-dose oral corticosteroids for the treatment of lupus nephritis [ Austin et al. In a subsequent study, patients were randomized to receive either IV MP monthly for 6 months, short-course IV cyclophosphamide monthly pulses for 6 months or long-course IV cyclophosphamide monthly pulses for 6 months followed by pulses every 3 months for 24 months in addition to oral prednisolone.
Sustained rise in creatinine and significantly higher probability of exacerbations were observed more often in the groups that received MP and the short-course cyclophosphamide compared with the group receiving long-course cyclophosphamide [ Boumpas et al. These findings were supported by longer duration studies that demonstrated that the combination of pulse cyclophosphamide and MP was more effective than the individual treatments without conferring additional risk for adverse events [ Illei et al.
IV cyclophosphamide became the standard of care, although unlicensed, for induction of remission in severe renal manifestations of lupus owing to the ability to slow the progression to end-stage renal failure [ Flanc et al.
Cyclophosphamide has been shown to be also effective for the treatment of nonrenal manifestations in patients with lupus nephritis [ Ginzler et al. The use of low-dose cyclophosphamide was investigated in the Euro-Lupus Nephritis Trial with a follow-up period of 10 years.
Ninety patients were randomized to receive NIH-like high-dose regimen six monthly pulses followed by two quarterly pulses or Euro-Lupus low-dose regimen six pulses of cyclophosphamide every 2 weeks at a fixed dose of mg. The cumulative risk of end-stage renal disease or death was not significantly higher in the latter group [ Houssiau et al.
Increasing evidence suggests that patients mainly Caucasian in trials to date may achieve disease control with lower cumulative doses of cyclophosphamide. Overall, established evidence for disease control and improved outcomes in lupus supports its use as a recognized standard of care. The risk of malignancy is reported to be higher with alkylating agents because of direct chromosomal damage and increased immune surveillance.
Longer duration of use greater than 2—3 years or high cumulative dose greater than 20 g increases the risk further [ Stillwell et al. Cancers that have been linked with cyclophosphamide use are haematological malignancies, namely myelodys-plastic syndromes, acute leukaemia and myeloma, and skin and bladder cancer amongst others [ Radis et al. MMF is an ester prodrug for mycophenolic acid, which inhibits inosinemonophosphate dehydrogenase, an enzyme involved in the de novo synthesis pathway of purine.
In vitro , it exerts its immunosuppressive effect by inhibiting B- and T-cell proliferation effects, causing suppression of antibody production and reduction of adhesion molecules that are necessary for the migration of lymphocytes to sites of inflammation [ Allison, ]. It has been used to prevent transplant rejection for over 10 years and currently is recognized as an alternative immunosuppressive agent to cyclophosphamide or azathioprine for the treatment of lupus nephritis.
Earlier studies showed that mycophenolate is as effective as IV cyclophosphamide for the induction of remission [ Chan et al. Following these results, a randomized, multicentre, prospective, open-label parallel group clinical trial, the Aspreva Lupus Management ALMS study, was set up to investigate the effects of mycophenolate and IV cyclophosphamide on the disease including the induction and maintenance of remission, prevention of flare in lupus nephritis class III, IV or V and assessed nonrenal manifestations as a secondary endpoint [ Ginzler et al.
Response rates at week 24 end of remission—induction phase were Efficacy of MMF for nonrenal manifestations was initially shown in case series and open-labelled studies [ Mok, ] and showed good response to treatment with recurrence or worsening of symptoms when the dose was tapered in the majority of patients who had haematological or dermatological disease.
More recent findings by [ Ginzler et al. The data is not as robust and convincing for the use of MMF in neuropsychiatric disease, with poor response noted in patients with transverse myelitis experiencing relapse despite ongoing maintenance therapy with MMF and low-dose corticosteroids. As a result, pulse therapy with cyclophosphamide remains the mainstay of treatment in severe central nervous system CNS disease and MMF should only be considered in patients who are refractory to, intolerant of, or reluctant to use cyclophosphamide.
Adverse events associated with MMF include gastrointestinal side effects such as diarrhoea, nausea and vomiting which can be minimized by reducing or splitting the dose. Some studies reported infection cellulitis, herpes zoster as a complication of its use, however this is a recognized complication of all cytotoxic agents.
MMF is more acceptable than cyclophosphamide in women of childbearing age as it does not cause gonadal toxicity. Patients, however, must be strongly advised against pregnancy during MMF treatment due to teratogenicity [ Anderka et al. In conclusion, MMF, although unlicensed in SLE, is increasingly being used for the induction and maintenance of remission of proliferative lupus nephritis and other severe manifestations of SLE. Further studies are required to confirm efficacy and more robust conclusions can only be drawn once long-term data following exposure to the drug become available.
So far, this review has focused on first-choice drugs for the treatment of SLE, but others include methotrexate [ Fortin et al. The calcineurin inhibitor, cyclosporin, has demonstrated good efficacy in the treatment of moderate proliferative nephritis and may be used as an alternative maintenance drug to azathioprine or as a steroid-sparing agent in SLE [ Griffiths et al. Owing to the risk of hypertension, blood pressure should be monitored closely [ Griffiths and Emery, ]. Tacrolimus has also been shown to be effective in the management of severe cutaneous disease and discoid lesions [ Bohm et al.
Some lupus cohorts have reported success using IV immunoglobulin in patients with acute disease flares including cytopenias, neurological involvement and secondary antiphospholipid syndrome, with concomitant sepsis, but this has not been confirmed in trials.