Cyclophosphamide (particularly intravenous pulsed therapy in combination with intravenous p ulsed steroid) is also effective in both inducing and maintaining remission in ANCA associa ted vasculitis (AAV). The standard regimes in AAV use 10 \200\22315 mg/kg doses of cyclopho sphamide given fortnightly for 6 weeks then 3-weekly for 9 weeks for re- mission induction. This regimen is also known as the CY- CLOPS regimen, since it is the regime that has been stud- ied in an ongoing large multicentre study of pulsed versus oral cyclophosphamide for remission induction Mechanism of action Cyclophosphamide is a pro-drug (an inactive cyclic phos- phamide ester of phosphoramide mustard) that undergoes an in vivo activation process. It is initially hep atically me- tabolized via cytochrome P450 to an equilibrium mixture of 4-hydroxycyclophosp hamide and aldophosphamide. In both AAV and SLE intravenous pulsed treatment is associated with less toxicity than cont inuous oral treat- ment with similar ef \201 cacy. Oral cyclophosphamide shows weak ef \201 cacy as mono- therapy in rheumatoid arthritis, bu t toxicity and side effects are severe. Aldophosphamide can be metabolized to phospho- ramide mustard (the active guanidine alkylat ing agent responsible for the therapeutic effects) and acrolein (the agent responsible for bladder toxicity). Aldophosphamide can also be inactivated via aldehyde dehydrogenase (ALDH ). The therapeutic effects of cyclophosphamide are therefore seen predominantly in cells wi th relatively low levels of ALDH. SLE Steinberg AD, Kaltreider HB, Staples PJ, et al. (1971) Cyclo- phosphamide in lupus neph ritis: a controlled trial. Ann In- tern Med 75: 165 \200\22371. The \201 rst randomized p lacebo con- trolled study of oral cyclophosphamide (3 \200\2234 mg/kg/day \200\223 a relat ively high dose regime) in lupus nephritis. 13 patients treated over 10 weeks \200\223 sig ni \201 cant bene \201 t in cyclophos- phamide treated group relative to placebo Austin H A, Klippel JH, Balow JE, et al. (1986) Therapy of lupus nephritis. N Engl J Med 314: 614 \200\22319. The \201 rst of the NIH studies, in 107 patients, using a variety of regimes. The study showed that IV pulsed cyclophosphamide (0.5 \200\2231 g/ m2) was signi \201 can tly better in proliferative lupus nephritis (reduced rate of end stage renal failure after 5 years) than oral steroids. The other regimes (oral cyclophospha- mide and azathioprine) w ere not shown to be statistically different from IV pulsed cyclophosphamide, but neither we re they shown to be signi \201 cantly better than oral steroids. The phosphoramide mustard moiety causes alkylation of guanidine nucleotides and inhibits DN A polymerization, thereby preventing cell replication in susceptible cell types. It is non- cell cycle phase speci \201 c. The most susceptible cell types are those which are most ra pidly dividing, such as those of the immune system and the bone marrow. The immunoregulatory effects of cyclophosphamide ap- pear to be mediated, in part, through effects on T cell activ- ity. There is some evidence that cyclophosphamide sup- presses Th1 -mediated immune responses whilst enhancing Th2-mediated responses. More recently there has been interest in a possible role of cyclophosphamide in modify- ing immune tolerance. Ther e is evidence, from the trans- plantation literature, that cyclophosphamide reduces CD4+CD2 5+ regulatory T cells which could modulate CHAPTER 19 DMARDs and immunosuppressive drugs 563 Boumpas DT, Austin HA, Vaughan EM, et al. (1992) Con- trolled trial of pulse methylpredniso lone versus two regi- mens of pulse cyclophosphamide in severe lupus nephritis. Lancet 340: 741 \200\2235. The second NIH study, in 65 patients, showing that pulsed IV cyclophosphami de [either over 6 months (0.5 \200\2231 g/m2 monthly) or 30 months (0.5 \200\2231 g/m2 mont hly \2276/12 then 3-monthly \2272 years) was better (as measured by increasing creatinine ) than pulsed IV methylprednisolone. Relapses were more common in the 6-month study group t han the 30-month group, but the 6-month group was not given any treatment to maintain remis sion. Gourley MF, Austin HA, Scott D, et al. (1996) Methylpred- nisolone and cyclophosphami de, alone or in combination, in patients with lupus nephritis. Ann Intern Med 125: 549 \200 \223 57. The third NIH study, in 82 patients, demonstrating the superior ef \201 cacy of c ombination treatment with pulsed IV cyclophosphamide (0.5 \200\2231 g/m2 monthly \2276/12 then 3- monthly \2272 years) and IV methylprednisolone, compared with pulsed IV methylpred nisolone alone. There was a trend to improved ef \201 cacy of combination treatment over p ulsed IV cyclophosphamide alone, but this failed to reach statistical signi \201 cance. Fl anc RS, Roberts MA, Strippoli, et al. (2004) Treatment for lupus nephritis. Cochrane Databa se Syst Rev 1: CD002922. A meta-analysis of all cyclophosphamide studies conclud- ing that cyclophosphamide treatment, in combination with steroids, is ef \201 cacious in proliferat ive lupus nephritis. A sig- ni \201 cant risk of gonadal failure (relative risk 2.18) was also noted. Yee CS, Gordon C, Dostal C, et al. (2004) EULAR random- ized controlled trial o f pulse cyclophosphamide and meth- ylprednisolone versus continuous cyclophosphamide and pr ednisolone followed by azathioprine and prednisolone in lupus nephritis. Ann Rheum Dis 63: 525 \200\2239. A randomized controlled study in 32 patients showing no signi \201 cant dif - ference in ef \201 cacy between pulsed treatment (10 mg/kg IV initially than pulsed oral treatment thereafter) and continu- ous treatment with cyclophosphamide (2 mg/kg/day \227 3 months) in remission induction and maintenance in renal SLE. However, the IV/pulsed regim e was better tolerated. Houssiau FA, Vasconcelos C, D \200\231Cruz D, et al. (2002) Im- mun osuppressive therapy in lupus nephritis: the Euro- Lupus Nephritis Trial, a randomized tria l of low dose ver- sus high dose intravenous cyclophosphamide. Arthritis Rheum 46: 2121 \200\22331. A controlled study of 90 patients showing that fortnightly pulsed low dose IV c yclophospha- mide (500 mg/2 weeks) was as effective in remission induc- tion as high dose t reatment (0.5 g/m2 increasing by 250 mg with each pulse to a maximum of 1500 mg/pulse), but with less infection risk. Barile-Fabris L, Ariza-Andraca R, Olguin-Ortega L, et al. (2005) Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe ne urological mani- festations in systemic lupus erythematosus. Ann Rheum Dis 64: 620 \200\223 5. A controlled study of 32 patients with severe neurological SLE. The study showed that, a fter an initial 3 g IV methylprednisolone treatment, pulsed IV cyclophospha- mide (0.75 g/m 2 monthly for 1 year and then 3-monthly thereafter for another year) was signi \201 cantly better (>20% neurological improvement) than pulsed IV methylprednis- olone (1 g monthly \2274/12, 2-monthly \2276/12, 3-monthly \227 1 year) alone. ANCA associated vasculitis Adu D, Pall A, Luqmani RA, et al. (1997) Controlled trial of pul se versus continuous prednisolone and cyclophospha- mide in the treatment of systemic vascu litis. Q J Med 90(6): 401 \200\2239. A randomized controlled study in 54 patients com- pari ng (A) pulsed cyclophosphamide (15 mg/kg) and prednisolone (10 mg/kg, every 2 weeks for 6 w eeks then every 3 weeks). (B) Continuous oral cyclophosphamide (2 mg/kg) for 3 months (foll owed by oral azathioprine) and prednisolone (0.85 mg/kg/day). The study showed that the con tinuous oral treatment regimen was associated with more toxicity and similar ef \201 cacy to the pulsed treatment regimen. Guillevin L, Cordier JF, Lhote F, et al. (1997) A prospect ive, multicenter, randomized trial comparing steroid and pulsed cyclophosphamide versus ste roids and oral cyclophospha- mide in the treatment of generalized Wegener \200\231s granulo - matosis. Arthritis Rheum 40: 2187 \200\22398. A randomized con- trolled study of 50 patie nts. All patients prior to randomization received \2273 IV pulses of methylpredniso- lone, oral prednisolone (1 mg/kg) and a single IV pulse of cyclophosphamide (0.7 g/m2). Thereaft er, the study com- pared oral cyclophosphamide (2 mg/kg/day) with IV pulsed treatment (init ially 0.7 g/m2 every 3 weeks reducing to 6-weekly) over 1 year. The study again showed simi lar ef \201 cacy but fewer side effects with the IV pulsed cyclo- phosphamide regimen. Hau bitz M, Schellong S, Gobel U, et al. (1998) Intravenous pulse administration of cyclophosph amide versus daily oral treatment in patients with antineutrophil cytoplasmic anti- body-as sociated vasculitis and renal involvement: a pro- spective, randomized study. Arthritis Rhe um 41: 1835 \200\22344. A randomized controlled study of 47 patients. All patients prior to randomization received \2273 IV pulses of methyl- prednisolone. Thereafter, the study com pared IV pulsed cyclophosphamide (0.75 g/m2 every month) with oral cy- clophosphamide (2 mg /kg/day) over 1 year. The study again showed similar ef \201 cacy, but fewer side effects with the IV pulsed cyclophosphamide regime. Rheumatoid arthritis Suarez-Almazor ME, Belseck E. Shea B, et al. (2000) Cyclo- phosphamide for rheumatoid arthritis. Cochrane Database Syst Rev 4: CD001157. A meta-analysis showing that oral cyclophosphamide is ef \201 cacious \200\223 bene \201 t was shown for symptom s and signs of rheumatoid arthritis (similar to sul- fasalazine, but less than methotrexate ). However, it was associated with signi \201 cant toxicity (haemorrhagic cystitis, GI sid e effects, bone marrow suppression, alopecia, amen- orrhoea and herpes zoster). Prescribing considerations What do I need to do before starting the treatment? Patient educ ation re: dosing, side effects, monitoring, drug interactions, etc. The risks of haemorrhagic cystitis, alopecia, bladder can- cer, sepsis, teratogenicity, inf ertility, and future malignancy should all be explicitly discussed with patients as part of the informed consent process before treatment is initiated. Neutropenic sepsis is a signi \201 cant risk of cyclophospha- mide treatment and patients should be cautioned to seek urgent medical advice if they become febrile or unwell dur- ing treatment. CYCLOPHOSPHAMIDE 564 Examples of common dose regimens for remission induction Note: induction regimes are genera lly given with IV Meth- ylprednisolone (500 mg \200\2231 g IV daily by intravenous infusion for 3 days) and concomitant oral steroid (usually a reduc- ing regime) \200\223 see below for details. Record at baseline FBC LFTs ESR or CRP Renal function Dose adjustment in renal impairment U rine dipstick Monitor disease activity and evidence of urothelial toxicity Either history o r serology Allows monitoring of changes Allows monitoring of changes Monitor disease activity A commonly used AAV regimen (based on BSR guidelines and the CYCLOPS study regimen) \200 15 mg/kg IV cyclophosphamide (maximum 1500 mg) (in 500 ml N. saline over 1 h (or longer if necessary)) every 2 weeks for 6 weeks then every 3 weeks for 3 months (reduce initial dose according to Table 1 for the elderly and those with a reduced creatinine clearance). Subseq uent maintenance therapy may be with a reduc- ing frequency of IV cyclophosphamide (e.g. 3 monthly) or with alternative immunosuppressive agents (e.g. aza- thioprine, mycophenolate, methotrexate) Varicella status Gonadal toxicity Males are at a signi \201 cant risk of oli- gospermia (p articularly those requir- ing more than 3 months of treat- ment). Cryopreservation of sperm should be offered to all males before the \201 rst pulse of treatment. At least 50% of m ales will develop azoosper- mia as a result of cyclophosphamide treatment using standard SL E/AAV protocols Table 19.1 Pulsed cyclophosphamide dose reductions according to age and creatinine/creatini ne clearance Creatinine >300 mol/l (calculated creatinine clearance <30 ml/min) Age Creatinine <300 mol/l (calculated creatinine clearance >30 ml/min) Females are at risk of premature ovarian failure although the threshold is thought to be hi gher than that for oli- gospermia in men. It is estimated that between 30 \200\22350% of wo men will experience permanent ovarian failure follow- ing 1 year of treatment with cyclopho sphamide \200\223 older women (>30 years) are at the greatest risk. There is no routine ov arian cryopreservation program for women, although some areas have experimental programs (f or preservation of both fertilized and unfertilized ova) and local policies should be inves tigated. <60 15 mg/kg/pulse 12.5 mg/kg/pulse 60 \200\22370 12.5 mg/kg/pulse 10 mg/kg/pulse >70 10 mg/kg/pulse 7.5 mg/kg/pulse A commonly used SLE regimen \200 0.75 \200\2231 g/m2 IV cyclophosphamide (maximum 1500 mg) (in 500 ml N saline over 1 h (or longer if necessary)) every month for 6 months (reduced to an initial dose of 0.5 g/m2 for the elderly, those at risk of leucopenia or those with a creatinine clearance of <30 ml/min ) \200\223 a commonly used regimen in lupus nephritis Subsequent maintenance therapy may b e with a reduc- ing frequency of IV cyclophosphamide (e.g. 3-monthly) or with alternative i mmunosuppressive agents (e.g. azathioprine, mycophenolate, methotrexate) What dose should I prescribe? Oral treatment Pulsed IV cyclosphosphamide is generally prefe rred to continuous oral treatment since it has been associated with less toxicity in a numb er of trial studies. However, continuous oral treatment is still used occasionally. Cyclophosphamide is available as 50 \200\223100 mg tablets Usual oral dose: 1.5 \200\2232 m g/kg/day rounded down to the nearest 50 mg. The maximum dose of oral cyclosphosphamide is u sually 200 mg (although doses up to 4 mg/kg have been used in some studies). The dose shoul d be reduced by 25% for patients >60 years and by 50% for patients >75 years. Usual practic e is to induce remission with 2 mg/kg for 3 months and to maintain remission with 1.5 mg/k g before changing to alternative maintenance therapy within 6 months. Other treatment considerations when prescribing IV pulsed cyclosphosphamide? MESNA MESNA reduces the urothelial toxicity of cyclophospha- mide. One dose (either oral or IV) i s given just prior to the infusion. Two further doses (usually oral) are then given 2 and 6 h post-infusion. \200 Dose 1: IV 20% of cyclophosphamide dose in 500 ml of N saline over 1 h, given just prior to cyclophosphamide treatment; OR PO 40% of cyclophosphamide dose just pre treatment. Dose 2: PO 40% of cyclophosphamide dose 2 h post- infusion. Dose 3: PO 40% of cyclophosphamide dos e 6 h post- infusion. Intravenous treatment \200 Dosage is calculated either on the basis of mg/kg (in AAV) or body surface area (in SLE). C alculation for body surface area (BSA) in m2 (Mosteller): BSA = square root {[weight (kg) \227 height (cm)]/3600} [usual adult BSA in men ( 1.9m2), in women ( 1.6m2)]. \200 CHAPTER 19 DMARDs and immunosuppressive drugs 565 Infection Cotrimoxazole 960 mg 30 \227/week (or 480 mg daily) should be given as prophylaxi s against PCP during treatment with cyclophosphamide. Antiemetic Prophylactic antiemetic usage is advised for IV cyclophos- phamide Prophylactic antiemetic usage: an example regimen \200 Monitoring Monitoring of WBC after IV cyclophosphamide Leucopenia/neutropenia and associate d sepsis is a signi \201 - cant risk. The WCC should therefore be monitored on days 0, 7, 10, and 14 post- \201 rst infusion and with any subse- quent infusions where there is a do se change. Thereafter, the WCC should be checked on the day of infusion or the previous day . Ondansetron 8 mg IV just prior to cyclophosphamide infusion Metoclopromide 10 mg po tds for 72 h post-infu- sion. If vomiting is problematic, despite the above regime, change from me toclopromide to post-dose oral ondansetron and oral domperidone for subsequent infusions. I f still problematic consider 1.5 mg haloperi- dol bd on day 1 and consider regular IV methy lpred- nisolone with cyclophosphamide(see below) If the total WCC fails to drop below 5 \227 109/l the dose of the subsequent infusion can be increased by 250 mg/m2 to a maximum of 1 g/m2 or 1500 mg. If the total WCC drops to a nadir of 2 \200\2233 \227109/l or the neutrophils counts drops to 1 \200\2231.5 \227 109/l the subsequent dose should be delayed until the neutrophil cou nt rises about 2 \227 109/l and the total WCC >4 \227 109/l. Subsequent doses should be r educed by 20% and monitored using the same WCC monitoring regime. IV glucocorticoids The \201 rst dose of induction regimes of cyclophosphamide are frequently given with \2273 pulses of IV methylpredniso- lone 500 mg \200\2231 g IV daily. If the total WCC drops to a nadir of 1 \200\2232 \227 109/l or the neutrophils counts drop s below 1 \227109/l the subsequent dose should be delayed until the neutrophil count rises about 2 \227109/l and the total WCC >4 \227109/l. Subsequent doses should be reduced by 40% and monitored using the same WCC monitoring regime. Subsequent infusions can be given with progressive reduction regimes. Subsequent infusions example \200 \200 \200 2nd pulse 500 mg IV methylprednisolone. 3rd pulse 250 mg IV methylprednisolone. IV steroid has both an anti-emetic effect and an immunosuppressive effect It should always be ensured that the WCC is recovering before administration of the next do se of cyclophospha- mide. Urgent FBC in patients with infection/fever Monitoring with oral cyclophosphamide \200 \200 FBC and urine. Leucopenia/neutropenia and associated sepsis are sig- ni \201 cant risks as is haemorrhagic cystitis. Monitor FBC and urine dipstick weekly for 4 weeks Monitor FBC an d urine dipstick fortnightly for 2nd/3rd months. Monitor FBC and urine dipstick monthly the reafter. Oral glucocorticoids An example reducing oral steroid regime, for use in con- junction with IV pulsed cyclophosp hamide regimes, is shown in Table 19.2. Doses may be reduced if IV methyl- prednisolone is used concomitantly. \200 Table 19.2 An example oral steroid reduction regime Side effects and what to discuss with your patient Common \200 Time from entry (weeks) Dosage (max 80 mg) 0 1 mg/kg/day \200\223 60 mg Nausea and vomiting: prophylactic antiemetic treat- ment should always be used in patients receiving cyclo- phosphamide. Hair loss (usually transient) can occur during treatment and patients should be forewarned of this. Mouth ulcers can also be problematic and patients sh ould be advised of the importance of oral hygiene. Skin rashes can occur and patients shoul d be aware of the increased risk of herpes zoster with cyclo- phosphamide/ \200\231steroid regimes. 1 0.75 mg/kg/day \200\223 45 mg 2 0.5 mg/kg/day \200\223 30 mg 3 0.4 mg/kg/day - 25 mg 4 0.33 mg/kg/day \200\223 20 mg 5 0.3 mg/kg/day \200\223 17.5 mg 6-12 0.25 mg/kg/day \200\223 15 mg Thereafter Reduce by 2.5 mg/month according to clinical response Haemorrhagic cystitis Patients should be advised of the importance of maintain- ing an adeq uate \202 uid intake when taking cyclophosphamide to reduce the chances of developing hae morrhagic cystitis (generally advise 8 \200\22310 glasses of water per day). They should al so be advised to report any blood in the urine. Hydration \200 Adequate hydration reduces the risk of haemorrhagic cystitis. Consider 500 ml IV N. saline pre-treatment (particularly if not receiving IV MESNA). Advise patients to drink 3 l/day fo r 3 days post-infusion. CYCLOPHOSPHAMIDE 566 Infection and bone marrow toxicity \200 Drug interactions Possible drug interactions with cyclophosphamide include: \200 Allopuri nol: there have been con \202 icting reports con- cerning an increased risk of marrow toxi city in patients taking allopurinol alongside cyclophosphamide. Phenytoin: cyclophosphamide redutes the absorption of phenytoin. Warfarin: both increased and decreased effects have b een reported with cyclophosphamide. Thiazide diuretics: prolonged leucopenia has been repor ted in patients treated with combination thiazide diuretics and cyclophosphamide, and thiaz ides should be used with caution in these patients As well as the risks of neutropenic sepsis highlighted above, there is an increased of all infections with cyclo- phosphamide treatments and the presentation of infec- tions may be a typical. Patients should be advised to urgently contact a health care professional for any unexplained illness during treatment with cyclophosphamide and an urgent FBC obtained. Evid ence of prior exposure to varicella (chicken pox) should, if possible, be con \201 rmed be fore commencing treatment and if necessary VZV serology checked. If non-immune advise patie nts to avoid contact and consider immunization pre-treatment. All patients should receive P CP prophylaxis with cotrimoxazole. There is also a risk of thrombocytopenia with cyclo- pho sphamide and patients should be advised to report unusual/easy bruising or other evidence o f bleeding (e.g. tarry stools, etc.). FAQs How long does it take to work? Advise patients that cyclophosphamide may take several weeks before the treatment takes eff ect. Infertility risk Cyclophosphamide causes infertility (both reversibly dur- ing treatment an d in a proportion of patients irreversibly (see above under gonadal toxicity) in both men a nd women. If possible, frozen storage of sperm or ova should be considered prior to commenc ing treatment. The risk of inducing irreversible infertility is signi \201 cantly greater in older patients and patients having more prolonged treat- ment courses. What if I want to get pregnant? Cyclophosphamide should not be used in pregnancy. Cyclophos phamide treatment should be discontinued at least 3 months prior to conception (in men and women). It is important for both men and women to take contra- ceptive precautions during c yclophosphamide treatment. Patients should be advised that even if the treatment stops a re gular monthly menstrual cycle it is still possible to conceive if appropriate contraception is not used. Malignancy \200 What about breast feeding? Cyclophosphamide treatment should be avoided in patients who are breast feeding Cyclophosphamide treatment has mutagenic/carcino- genic potential due to the alkylation of DNA. The incidence of all malignancies is increased in patients with SLE/AAV treated with c yclophosphamide (SIR approx. 2). The incidence of haematopoietic malignancy (most notably a cute myeloid leukemia) is significantly increased (SIR approx. 20) compared with the expect ed levels. Cyclophosphamide is also associated with an increased long-term risk of bladder cancer (SIR approx. 4) and non-melanoma skin cancer (SIR approx. 5). The risks of all malig nancies are dose-dependent and malignancies can occur several decades after treatment so pa tients should be monitored long term. What about immunizations? \200 Live attenuated vaccines need to be avoided by patients on cyclophosphamide treatment: yell ow fever, MMR and rubella, BCG, oral polio, oral typhoid. Other vaccines are not a problem. Patients should be advised to have an annual in \202 uenza immunization since they are at an increased risk of in \202 u- enza. \200 Can I drink alcohol? Alcohol does not interfere with cyclophosphamide Contraception Cyclophosphamide is teratogenic due to the alkylating ef- fects, and both mal e and females should use contraception during and for 3 months after cyclophosphamide treat - ment. Patients should be advised that even if the treatment stops a regular monthly menst rual cycle, it is still possible to conceive if appropriate contraception is not used. This page intentionally left blank BIOLOGICS 568 Biologics: anti-TNF (in \202 iximab, etanercept, adalimumab), anti-CD20 (rituximab), anti- IL-1 (anakinra), CTLA4 \200\223Ig (abatacept), and anti-IL-6R (tocilizumab) History In \202 iximab, adalimumab and etanercept (Anti-TNF (antibodies and recombinant so luble receptor)) \200 Abatacept [anti-T cell (CTLA4-Ig fusion protein)] \200 1993: CTLA4 (cytotoxic T lymphocyte antigen 4) is iden- ti \201 ed as a CD28-like molecule expressed on T cells, fol- lowing activation, which inhibits T cell activation when it int eracts with the CD80/86 ligand on antigen presenting cells. This is in contrast to the CD28 /CD80/86 interac- tion which is stimulatory for T cells. 1994: CTLA4-Ig fusion protein is s hown to inhibit syno- vial T cell proliferation in vitro (by inhibiting CD28/ CD80/86 inter actions). 1995: CTLA4-Ig is shown to inhibit in \202 ammatory arthri- tis in a rat model. 2003: CTLA4-Ig is shown to be ef \201 cacious in the treat- ment of rheumatoid arthritis. 1890s: Dr William Coley identi \201 es that bacterial infec- tions can trigger the immune system to produce anti- tumor effects. 1975: tumor necrosis factor is identi \201 ed as a monocyte derived cytotoxic factor by Dr Lloyd Old. 1986: tumor necrosis factor is demonstra ted to have detrimental effects on cartilage in vitro. 1988: elevated levels of TNF are dem onstrated in both synovial \202 uid and serum of patients with rheumatoid dis- ease. 1992 : chimeric anti-TNF antibodies are shown to be ef \201 - cacious in mouse models of in \202 ammatory arthritis. 1993: chimeric anti-TNF antibodies are shown to be ef \201 - caci ous in patients with rheumatoid arthritis. 1997: recombinant human TNF receptor (etanercept ) is shown to have ef \201 cacy in rheumatoid arthritis. 2002: adalimumab (a non-chimeric anti-TNF antibody) is developed for treatment of rheumatoid arthritis. NICE TAG32 supports the use of anti-TNF in rheumatoid arthritis. Tocilizumab (Anti IL-6 (non-stimulatory anti-receptor antibody)) \200 1988: interleukin 6 levels are shown to be elevated in rheumatoid arthritis synovial fluid and serum. The Interleukin 6 receptor is isolated. 2000: Tocilizumab (an anti-IL-6 receptor antibody) is shown to be ef \201 cacious in multicentric Castleman \200\231s dis- ease (a condition characterized by high IL-6 levels). 2002: Tocilizumab is shown to have ef \201 cacy in rheuma- toid arthritis Rituximab (anti B cell (anti-CD20 antibody)) \200 1992: chimeric anti-CD20 antibodies are shown to deplete B cells in mouse models. 1997: chi meric anti-CD20 antibody (Rituximab) is used successfully in the treatment of lymphoma. 200 2: Rituximab is shown to have ef \201 cacy, in different studies, in ANCA associated vascu litis, SLE, and rheuma- toid arthritis. 2007: NICE TAG126 supports the use of rituximab in rheumatoid arthritis patients who have failed anti-TNF. Possible mechanisms of action Conventional DMARDs are molecules that characteristi- cally h ave a multiplicity of anti-inflammatory actions. By contrast, the biologics are variants of the endogenous proteins of the immune system (usually antibodies), which are bioengineered to speci \201 cally target individual compo- nents of the in \202 ammatory response. Mos t commonly, these biologics target cytokines or co-stimulatory mole- cules, which have prev iously been demonstrated to be important in the in \202 ammatory response. Antibodies may be chimeric (usually incorporating a murine binding region (Fab fragment), which gives the molecule it \200\231s speci \201 city, and a human signaling component (Fc region) \200 \223 see Figure 19.7. The mechanisms of action and the molecular structure of the common bi ologics used in rheumatology are shown in Table 19.3. Anakinra [anti IL-1 (IL-1 receptor antagonist)] \200 1982: IL-1 is shown to be important in the pathogenesis of rheumatoid arthritis. 1984: IL-1 receptor antagonist, a naturally occurring antagonist of IL-1, is identi \201 ed. 1991: r ecombinant IL-1 receptor antagonist is shown to be ef \201 cacious in a rabbit model of in \202 ammatory arthri- tis. 1996: preliminary data suggest some bene \201 t for recom- bi nant human IL-1 receptor antagonist (anakinra) in rheumatoid arthritis. 1996-2000: several studies show limited ef \201 cacy with anakinra for symptoms but some reduction in radio- graphic progression in rheumatoid arthritis. 2003: NICE TAG72 advises against the use of an akinra for rheumatoid arthritis. CHAPTER 19 DMARDs and immunosuppressive drugs 569 Table 19.3 A table of the biologics indicating their structure and their mechanism of actio n Generic Name Trade Name Protein Structure Mechanism Of Action In \202 iximab Remicade Chimeric anti-TNF monoclonal antibody Binds both membrane bound and circulating TNF preventing it \200\231s binding to the TNF re ceptor Adalimumab Humira Humanized anti-TNF monoclonal antibody Binds both membrane bound and circulating TNF preventing it \200\231s binding to the TNF re ceptor Etanercept Enbrel Recombinant human TNF receptor Binds circulating TNF preventing it \200\231s binding to the TNF receptor Rituximab Mabthera Chimeric anti-CD20 monoclonal antibody Binds CD20 on B cells resulting in B cell depletion through complement mediated cytotoxicit y (interacting with the Fc component of the antibody) Abatacept Orencia Recombinant Immunoglobulin/ CTLA4 fusion protein Binds with high af \201 nity to CD80/86 on antigen presenting cells, preventing T cell act ivation through CD28 interactions with CD80/86 Anakinra Kineret Recombinant human IL-1 receptor antagonist Binds to the IL-1 receptor and therefore prevents activation through IL-1 binding Tocilizumab Actemra Recombinant human anti-IL-6 receptor antibody Binds to but does not activate the IL-6 receptor. Prevents binding by constitutively secret ed IL-6 Binding component The section that binds the relevant area. This may be the binding section of a mouse antibody (chimeric antibodies (e.g. infliximab, tocilizumab)), a recombinant pr otein (e.g CTLA-4 protein (abatacept), the human antibody binding region (adalimumab)). Signaling component The section that interacts with other components of the immune response (e.g complement, immunoglobulin receptors). This is usually the Fc component of immunoglob ulin. Figure 19.8 A \201 gure showing the characteristic structure of the biologics with a bind ing component and a signaling component. Evidence base: the clinical trials with biologics Summary Anti-TNF There is good evidence f or anti-TNF therapy, in rheuma- toid arthritis in both symptom relief and prevention of ra- diographic progression/structural damage. Radiographic bene \201 t may be seen even in th e absence of symptomatic relief. All anti-TNF treatments are more effective if given as com bination treatment with methotrexate. There appears to be similar ef \201 cacy for all thr ee anti-TNF treatments al- though the in \202 iximab has more robust evidence of ef \201 cacy in early disease, in inducing disease remission. Trial results in ANCA associated vasculitis are con \202 icting with some evidence in favo r of in \202 iximab but a large trial with etanercept showing no bene \201 t. There is limited data suggesting ef \201 cacy for in \202 iximab in ocular Beh et \200 \231s and in GCA, but further studies are needed in these areas. Rituximab (anti-CD20 (B cell depletion) There is good evidence for rituximab in rheumatoid arthri- tis, SLE and ANCA-associated vasculitis. In rheumatoid arthritis, where the evidenc e base is most robust, it is effective in combination with methotrexate and is effective in patients responding inadequately to anti-TNF. There also is good evidence for anti-TNF treatment of patients with psoriatic arthritis and ankylosing spondylitis. BIOLOGICS 570 Anakinra [IL-1 receptor antagonist (Anti-IL-1)] Although studies have shown clinical ef \201 cacy, the symp- tomatic improvements seen are relatively small. The stud- ies undertak en have shown ef \201 cacy in reducing radio- graphic progression. Smolen JS, Van Der Heijde DM, St Clair EW, et al. (2006) Predictors of joint damage in pati ents with early rheuma- toid arthritis treated with high-dose methotrexate with or without concomitant in \202 iximab: results from the ASPIRE trial. Arthritis Rheum 54:702 \200\223 10. The ASPIRE study \200\223 a dou- ble-blind controlled study showing that in \202 ixim ab treat- ment (in combination with methotrexate) reduced radio- graphic progression of dis ease irrespective of the in \202 ammatory response. Weinblatt ME, Kremer JM, Bankhurst AD (1999) A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion prote in, in patients with rheumatoid arthritis re- ceiving methotrexate. N Engl J Med 340(4): 25 3 \200\2239. The \201 rst DBPCS (89 patients) with etanercept which showed the ef \201 c acy of etanercept when used as combination treat- ment with methotrexate over 6 months of t reatment Keystone EC, Schiff MH, Kremer JM, et al. (2004) Once- weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, ran- domized, double-blind, placebo-controlled trial. Arthritis Rheum 50: 353 \200\22363. A DBP CS in 420 patients showing that 50 mg weekly of etanercept was of equivalent ef \201 cacy to 25 mg twice weekly. Weinblatt ME, Keystone EC, Furst DE (2003) Adalimumab, a fully human anti-tumor necrosis factor A monoclonal an- tibody, for the treatment of rheumatoid arthri tis in patients taking concomitant methotrexate: the ARMADA trial. Ar- thritis Rheum 48: 35 \200\22345. The ARMADA study - the initial DBPCS with adalimumab (271 patients) showing th e ef \201 - cacy of a number of different dosage regimes, every other week, in combination with methotrexate, over 6 months. Subsequent studies showed a reduction in radiographic pr ogression of the disease, as well as symptom control. Furst DE, Schiff MH, Fleischmann RM, et al. (2003) Adalim- umab, a fully human anti tumor necrosis factor-A monoclo- nal antibod y, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis : results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthri- tis). J Rheumatol 30: 2 563 \200\22371. The STAR study \200\223 a DBPCS in 636 patients showing that 40 mg every o ther week of adalimumab was an effective and same treatment when added to conventional trea tment in patients showing only partial responses to other treatment. Abatacept [CTLA4-Ig Fusion protein (Anti T cell)] Studies have shown ef \201 cacy in patie nts partially responsive to conventional DMARDs, as well as those partially responsive to a nti-TNF, in combination with conventional DMARDs (generally methotrexate) Tocilizumab (Anti-IL6 receptor antibody) Studies have shown ef \201 cacy for both symptom relief and radiographic progression in patients previously inadequately responsive to conve ntional DMARDs. Improved ef \201 cacy is seen when used in combination with methotrexate. Anti-TNF (In \202 iximab, etanercept and adalimumab) Rheumatoid arthritis Elliott MJ, Main i RN, Feldmann M, et al. (1994) Randomized double-blind comparison of chimeric monoclonal a ntibody to tumor necrosis factor A (cA2) versus placebo in rheu- matoid arthritis. Lancet. 344(8930): 1105 \200\22310. The original DBPCS of anti-TNF treatment demonstrating the ef \201 cacy of in \202 iximab as a single injection in rheumatoid arthritis Lipsky P, van de r Heijde, et al. (2000) In \202 iximab and metho- trexate in the treatment of rheumatoid a rthritis. Anti- Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therap y Study Group. N Engl J Med 343: 1594 \200\223602. The ATTRACT study \200\223 a DBPCRS of 428 pa- tients showing the ef \201 cacy of in \202 iximab in combination with methotrexat e, in both symptom control and radio- graphic progression. Smolen JS, Han C, Bala M, et al. (2005) Evidence of radio- graphic bene \201 t of treatment with in \202 iximab plus meth o- trexate in rheumatoid arthritis patients who had no clinical improvement: a detailed sub analysis of data from the anti- tumor necrosis factor trial in rheumatoid arthritis with co ncomitant therapy study. Arthritis Rheum 52: 1020 \200\22330. A follow-up from the original ATTRACT study showing that even in patients who failed to respond clinically there was evi dence of improved radiological outcome. Quinn MA, Conaghan PG, O \200\231Connor PJ, et al. (2005) Very early treatment with in \202 iximab in addition to methotrex- ate in early, po or-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained bene \201 t after in \202 iximab withdrawal: results from a tw elve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum 52: 27 \200 \22335. A DBPCS showing that early treatment with in \202 iximab (in patients with less th an 12 months of symptoms) could induce a disease remission which was sustained despite stop ping treatment. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. (2005) Clini cal and radiographic outcomes of four different treatment strategies in patients with early rheu- matoid arthritis (the BeSt study): a randomized controlled trial. Arthritis Rheum 52 : 3381 \200\22390. The BeSt study showing that early combination treatment, with methotrexa te and in \202 iximab, resulted in more rapid improvement clinically and joint damage supp ression than sequential monother- apy or step-up combination therapy. Psoriatic arthritis Antoni CE, Kavanaugh A, Kirkham B, et al. (2005) Sustained bene \201 t s of in \202 iximab therapy for dermatologic and articu- lar manifestations of psoriatic a rthritis: results from the in \202 iximab multinational psoriatic arthritis controlled tri al (IMPACT). Arthritis Rheum 52: 1227 \200\22336. The IMPACT study \200\223 a double-blind placebo controlled cross-over treatment study (104 patients) showing that in \202 iximab (5 mg/kg) is ef \201 cacious in patients with psoriatic arthritis and psoriasis Mease PJ, Gotte BS, Metz J, et al. (2000) Etanercept in the treatment of psoriatic arthritis and psor iasis: a randomized trial. Lancet 356(9227): 385 \200\22390. A DBPCS in 60 patients with ps oriatic arthritis (and psoriasis) showing the ef \201 cacy of etanercept monotherapy over a 12-week treatment period. Gladman DD, Mease PJ, Ritchlin CT, et al.(2007) Adalimumab for long-term treatment of psoriatic arthritis: forty- eight week data from the adalimumab effe ctiveness in psori- atic arthritis trial. Arthritis Rheum 56: 476 \200\22388. The ADEPT CHAPTER 19 DMARDs and immunosuppressive drugs 571 study \200\223 a double blind placebo controlled trial (292 patients) with showing ef \201 cacy for adalimumab over a 6-month study period for both psoriatic arthritis and psori asis. SLE Leandro MJ, Cambridge G, Edwards JC, et al. (2005) B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheu- matol (Oxf) 44: 1542 \200\2235. One of several open-label studies showing ef \201 cacy of rituximab in SLE. In this study 2 doses of rituximab (1 g) were given 2 weeks apart. Each r ituximab dose was given with intravenous cyclophosphamide (750 mg) and methylprednisolone ( 250 mg). Responses were maintained over at least 6 months.