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. Ankylosing spondylitis Braun J, Brandt J, Listing J, et al. (2002) Treatment of active anky losing spondylitis with in \202 iximab: a randomized con- trolled multicentre trial. Lance t 359(9313): 1187 \200\22393. A DBPCS in 70 patients with ankylosing spondylitis showing ef \201 cacy of in \202 iximab over a 3-month treatment period. Davis JC Jr, Van Der Heijde D, Braun J, et al. (2003) Recom- binant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum 48: 32 30 \200\2236. A DBPCS in 277 patients with ankylosing spondylitiis showing the ef \201 cac y of etaner- cept monotherapy over a 6-month treatment period ANCA-associated vasculitis Stasi R, Stipa E, Del Poeta G, et al. (2006) Long-term obser- va tion of patients with anti-neutrophil cytoplasmic anti- body-associated vasculitis treated with rituximab. Rheuma- tol (Oxf) 45: 1432 \200\2236. An open label prospective study, in 1 0 patients with relapsed ANCA associated vasculitis, show- ing ef \201 cacy for rituximab (375 mg/m2 weekly for 4 weeks) in inducing remission. ANCA associated vasculitis Booth A, Harper L, Hammad T, et al. (2004) Prospective study of TNFA blockade with in \202 iximab in anti-neutrophil cytoplasmic antibody-associated syste mic vasculitis. J Am Soc Nephrol 15: 717 \200\22321. An open label prospective study in 28 patients with ANCA associated vasculitis showing ef \201 cacy in disease remission with in \202 iximab. A signi \201 cant relapse rate was seen and further studies are required. W egener \200\231s Granulomatosis Etanercept Trial (WGET) Re- search Group (2005) Etanercept plus standard therapy for Wegener \200\231s granulomatosis. N Engl J Med 352(4): 351 \200 \22361. A randomized placebo-controlled study of 180 patients with Wegener \200\231s granul omatosis which failed to show any signi \201 cant bene \201 t for etanercept in the maint enance of remission. Anakinra (IL-1 receptor antagonist) Rheumatoid arthritis Cohen SB, Moreland LW, Cush JJ, et al. (2004) A multicen- tre, double blind, randomized, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid ar thritis treated with background methotrexate. Ann Rheum Dis 63: 1062 \200\2238. A DBPCT (50 6 patients) of 100 mg daily of anakinra as combination treatment with methotrexate. Althoug h sta- tistically signi \201 cant clinical responses were seen at 24 weeks, compared with placebo, the magnitude of the dif- ference was relatively small. Other studies have shown i mproved radiographic outcome. Beh et \200\231s disease Ohno S, Nakamura S, Hori S, et al. (2004) Ef \201 cacy, safety, and pharmacokinetics of multiple administration of in \202 ix- imab in Beh et \200\231s d isease with refractory uveoretinitis. J Rheumatol 31: 1362 \200\2238. A small open label st udy showing ef \201 cacy for in \202 iximab in Behcet \200\231s complicated by uveitis Abatacept (CTLA4-Ig Fusion protein) Rheumatoid arthritis Kremer JM, Westhovens R, Leon M, e t al. (2003) Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 349: 1907 \200\22315. The AIM study \200\223 a double blind placebo con- trolled, dose \201 nding trial (339 patients), showing clinical ef \201 cacy of 10 mg/kg of abatacept (days 1, 15, 30, and there- after monthly) in combi nation with methotrexate (in pa- tients inadequately responsive to methotrexate). Kremer JM , Dougados M, Emery P, et al. (2005) Treatment of rheumatoid arthritis with the selective c ostimulation modulator abatacept: twelve-month results of a phase iib, double-blind, random ized, placebo-controlled trial. Arthritis Rheum 52: 2263 \200\22371. The ATTAIN trial \200 \223 a DBPCS (258 patients), showing clinical ef \201 cacy of 10 mg/kg of abatacept (days 1, 15, 29, and thereafter monthly) over 6 months in combination with conventional DMARDs (7 5% of these were methotrexate) in patients previously inadequately responsive to anti-TNF t reatment. RITUXIMAB (anti-CD20) Rheumatoid arthritis Edwards JC, Szczepanski L, Szechinski J, et al. (2004) Ran- domised ef \201 cacy of B-cell-targeted therapy with rituximab in patients wit h rheumatoid arthritis. N Engl J Med 350:2572 \200\22381. The original randomized controlle d study of rituximab treatment, of rheumatoid arthritis, (161 patients) demonstrating the e f \201 cacy of 2 infusions of rituximab ei- ther as monotherapy or in combination with cyc lophos- phamide or methotrexate. Emery P, Fleischmann R, Filipowicz-Sosnowska, et al. (2006 ) The ef \201 cacy and safety of rituximab in patients with active rheumatoid arthritis de spite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo- con trolled, dose-ranging trial. Arthritis Rheum 54: 1390 \200\223400. The DANCER study \200 \223 a DBPCS (465 patients over 6 months) showing that Rituximab 500mg on days 1 and 15 was as efficacious as 1000 mg on days 1 and 15. Treatment was given as combination treatment w ith methotrexate. Cohen SB, Emery P, Greenwald MW, et al. (2006) Ritux- imab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, rand om- ized, double-blind, placebo-controlled, phase III trial evalu- ating primary ef \201 c acy and safety at twenty-four weeks. Ar- thritis Rheum 54: 2793 \200\223806. The REFLEX stu dy \200\223 a DBPCS (519 patients) showing that rituximab was effective treat- ment (in co mbination with methotrexate over 6 months) in anti-TNF non responders. Tocilizumab (anti-IL-6 receptor antibody) Rheumatoid arthritis Maini RN, Taylor PC, Szechin ski J, et al. (2006) Double-blind randomized controlled clinical trial of the interleukin-6 re- ceptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 54: 2817 \200\22329. The CHARISMA Study \200\223 a randomized dose \201 nding placebo controlled trial (359 patients) show ing that 4 \200\2238 mg every 4 weeks of tocili- zumab is symptomatically ef \201 cacious in patients who have inadequately responded to methotrexate. Improved re- sponses were seen in combination with methotrexate than when tocilizumab was used as monotherapy. BIOLOGICS 572 Nishimoto N, Hashimoto J, Miyasaka N, et al. (2007) Study of active controlled monotherapy used for rheumatoid ar- thritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radi ographic bene \201 t from an \227 ray reader-blinded ran- domised controlled trial of toc ilizumab. Ann Rheum Dis 66: 1162 \200\2237. The SAMURAI study \200\223 a randomized contro lled study (306 patients) showing improved radiographic out- come with tocilizumab monother apy (8 mg/kg monthly) over 12 months compared with conventional DMARD treatment. is an increased risk of extrapulmonary disease and dis- seminated infection. Appropriate screening (see Figure 19.9) should be un- dertaken to exclude infection with TB before commencing treatment with anti-TNF. If there is evidence of (or suspicion of) latent TB prophy- lactic treatment with isoniazid should be instituted (after consultation with a respiratory or infectious diseases physici an) Patients should be advised, when on treatment, to report any symptoms suggestive of TB (cou gh, weight loss or fever). Prescribing considerations What do I need to do before starting biologic treatment? \200 Monitoring and DMARDs Ensure appropriate DMARD monitoring is in place. Note: In addition to improved ef \201 cacy when methotrex- ate is used in combination with all biologics, the chimeric biologics (in \202 iximab, rituximab and tocilizumab) are capa- ble of inducing a n antibody response [human anti-chimera antibodies (HACA)]. This response appears to be red uced by maintenance treatment with conventional DMARDs. Patient education re: dosing, side effects, monitoring, drug interactions, etc. Patients sh ould be warned of the risks of infusion reac- tions with IV preparations, the potential ris ks of malig- nancy and the infection risks (see below). Ensure there is no history of SLE o r multiple sclerosis before prescribing anti-TNF. Anti-TNF treatment should also be avoided in moderate \200\223 severe heart failure. Check weight (to calculate doses). What dose should I prescribe? Anti-TNF 1. Rheumatoid arthritis \200 Subcutaneous injections \200 In \202 iximab: 3 mg/kg, 0, 2 and 6 weeks then 8 weekly by intravenous infusion. Adalimuma b: 40 mg alternate weeks subcutaneously. Etanercept: 25 mg twice weekly subcutaneously or 5 0 mg weekly subcutaneously. Discuss with the patients the requirements for self injec- tion and arrange appropriate del ivery/support/cvollec- tion at home. Ensure patient is happy and competent to self inject. Train/educate patient on: injection technique, sharps disposal, appropriate storage/disposa l of treatment. Provide telephone helpline support for the patients. Warn patient,s at base line that if they fail to respond ade- quately to the treatment it will need to be disconti nued. \200 \200 2. Ankylosing spondylitis \200 \200 In \202 iximab: 5 mg/kg 0,2 and 6 weeks then 8 weekly by intravenous infusion. Adalimumab: 40 mg alternate weeks subcutaneously. Etanercept: 25 mg twice weekly subcutaneously. \200 Record baseline disease activity DAS28, BASDAI, SLEDAI, BILAG, BVAS (or other appropriate d isease monitoring tools). FBC 3. Psoriatic arthritis \200 In \202 iximab: 5 mg/kg 0,2 and 6 weeks then 8 weekly by intravenous infusion. Adalimumab: 40 mg alternate weeks subcutaneously. Etanercept: 25 mg twice weekly subcutaneously. \200 Consider monitoring neutrophils with Anakinra Renal function Monitoring disease activity (SLE, AAV) ESR or CRP Monitoring disease activit y Radiographs Assessing disease progress ANCA ANA/ENA Rituximab 1. Rheumatoid arthritis \200 Dose: 1 g by intravenous infusion on days 0 and 14. Dose can then be repeated after >6 mont hs if symptoms recur and B cell have reconstituted (ideally recheck B cell lev- els by meas uring CD19 levels in PBMC). Rituximab should be given with 100 mg methylpred- nisolone IV a nd antihistamine/paracetamol PO to pre- vent infusion reaction. Rituximab should be given w ith regular methotrexate in rheumatoid arthritis If treating vasculitis In patients for anti-TNF (due to the risk of developing ANA/SLE). Infection risks The major concern, with biologic treatments, is infection risk and serious life-threatening infections are a risk with all biologics. In comparison with the anti-TNF treatments, the risks seem to be less with rituximab, abatacept and tocili- zumab but the d ata is more limited than that with anti-TNF. Do not start biologic treatments in patients w ith active infection or signi \201 cant recurrent infections. 2. SLE Dose: different studies have used different doses and there is no agreed regime. An evidence-based regime is: Days 0 + 14 Rituximab 1 g IVI Cyclophosphamide 750 mg IVI With high dose oral prednisolone Patients receiving biologic treatments should be advised against eating un-pasteurized milk , mold ripened soft cheeses (e.g. camembert and brie), blue cheeses, pate and raw egg due t o the risks of Listeria and Salmonella infection. For anti-TNF treatment there is a particu lar risk of reac- tivation of latent TB. Furthermore, when TB occurs, there Rituximab should be given with 100 \200\223250 mg methylpred- nisolone IV (higher doses of steroid have been used in CHAPTER 19 DMARDs and immunosuppressive drugs 573 History - exclude prior TB exposure - previous TB treatment? Clinical examination Baseline chest radiograph Consider tuberculin skin test (or T spot) Stratify risk of TB exposure \210\227 Abnormal CXR or History of TB or Positive Tuberculin (no BCG) High TB risk stratification \210\227 Normal CXR or No History of TB or Previous BCG AND low TB risk stratification \210\227 Refer to respiratory physician Adequately treated prior TB (Inactive disease) Inadequately or non treated prior TB Commence treatment and observe Commence treatment and observe Consider chemoprophylaxis Figure 19.9 Screening Patients for TB (* see British Thoracic Guidelines 2004). Side effects and what to discuss with your patients Infection risk (see above) \200 SLE studies) and antihistamine PO to prevent infusion reaction. Anakinra 1. Rheumatoid arthritis 100 mg daily by subcutaneous injection. Advise patients of the increased infection risk (see above) and to seek medical advice earl y, in the event of unexplained illness. Advise patients to avoid eating un-pasteurized milk , mold ripened soft cheeses (e.g. camembert and brie), blue cheeses, pate and raw egg due t o the risks of Listeria and Salmonella infection. Abatacept 1. Rheumatoid arthritis \200 10 mg/kg by intravenous infusion, 0, 2 and 4 weeks, there- after every 4 weeks. Abatacept s hould be given as combination therapy with a DMARD (methotrexate is advised) Infusion reactions These characteristically occur during or shortly after the initial infus ions of the intravenous biologics. They are char- acterized by high temperatures, nausea, s haking, headaches, skin rashes/itching. Occasionally, there may be hypoten- sion, shortness of breath, and wheeze. Usually these can be controlled by stopping the infusion for a peri od of time then slowing the infusion rates and management with anti- histamines, paracetamo l and corticosteroids (see below). Tocilizumab 1. Rheumatoid arthritis \200 \200 \200 4 \200\2238 mg/kg every 4 weeks (8 mg/kg is the standard dose). Given by IV infusion. Tocil izumab should be given as combination therapy with a DMARD (methotrexate is advised). Important drug interactions There are currently no recognized drug interactions with the bi ologics. However the treatments are relatively new and any suspected drug interaction shoul d be reported. Injection site reactions A local skin reaction can occur at sites of subcutaneous injection s (with adalimumab, etanercept and anakinra). These occur in 20 \200\22330% of patients. Th ere is local redness, swelling, pain, and itching which can persist for up to 1 week after administration. The severity of these local reac- tions often reduces over time with treatm ent. The reac- tions can be reduced by frequently changing the area used for injections and by cooling the area (e.g. with a cold wet towel) post-injection. Monitoring \200 Patients on biologics should be monitored initially at least every 3 months, for response t o treatment. In the UK appropriate monitoring data should be submitted to the BSR Biologics Register http://www.medicine.man- chester.ac.uk/arc/BSRBR/ In patients on anti-TNF treatme nt a CXR should be undertaken after 3 months of treatment and thereafter annually. An ANA s hould be monitored annually. Patients should be assessed before all infusions to ensure the re is no evidence of infection or developing side effects. Autoimmune reactions The development of anti-nuclear antibodies and lupus-like syndromes ha ve been reported in patients on anti-TNF treatment. The incidence of demyelinating disease is also possibly increased in patients on anti-TNF treatment. These reactions are thought t o be due to altered cytokine balance BIOLOGICS 574 should be avoided during pregnancy. Women of child bear- ing age should therefore be advise d on contraception. Fur- thermore, most biologics should be discontinued 3 \200\2236 months prior to conception, although rituximab should be discontinued 12 months before. It is imp ortant to also be aware of the risks of the concomitant DMARDs and advise accordingly. and the development of symptoms suggestive of either SLE or demyelination should trigger di scontinuation of the treatment. An ANA should be documented at baseline and during treatmen t in patients having anti-TNF treatment. Congestive cardiac failure Patients with moderate or severe congestive cardiac failure (NYH A Grade 3 or 4) should not be treated with anti-TNF due to the increased risk of CCF noted in trials with both in \202 iximab and etanercept. If a patient develops CCF or experience worsening of mild symptoms, whilst being treated with anti-TNF the treatment should be dis contin- ued. Patients should therefore be advised to report any worsening dyspnoea or oedem a and should be monitored regularly. What about breast feeding? As for the pregnancy associated risks, the data is limited, but the advice should be to avoid biologic treatments whilst breast feeding. What about immunization?? \200 Live attenuated vaccines need to be avoided by patients taking on biologic treatments (i.e. yellow fever, MMR and rubella, BCG, oral polio, oral typhoid). Other vaccines will not be 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. A pneumovax inoculation is also advisabl e, espe- cially in the elderly. FAQs How long does it take to work? This is dependent on the mechanism of action of the bio - logic in question. Anti-TNF treatments characteristically act quickly (the infusion treat ments can work within a few days) and a response should certainly be evident within 12 week s of treatment. By contrast the response to abatacept and rituximab can take longer. 3 \200 \2236 months may be required be- fore the bene \201 ts become apparent with these latter a gents. \200 Can I drink alcohol? There is no known interaction of the biologics with alco- hol, but pat ients should be advised accordingly for the DMARD treatments (particularly if taking methot rexate). What if I miss a dose of a subcutaneous injection? Inject the missed dose as soon as possib le and then give the next dose as usual What to do if side effects occur Infusion reactions Mild infusion reaction (mild fever, sha king, itching) Slow rate of infusion and give oral paracetamol 1 g and anti-histamine (e.g. chlorpheniramine (piriton) 4 mg) What if I want to get pregnant? Little is known about the toxicity/teratogenicity of the bi o- logic treatments during pregnancy. There are reports of successful healthy deliveries bu t in general the treatments Patient on anti-TNF treatment admitted with pyrexia 1) Stop anti-TNF 2) Assess clinically for common infections 3) Arrange CXR 4) Send appropri ate cultures (blood, urine, sputum etc) 5) Treat as indicated 6) Recommence anti-TNF 2-4 we eks post resolution of infection No obvious source identified but continued pyrexia INVESTIGATE FOR POSSIBLE TUBERCULOSIS 1) Liaise with local microbiologists and 1) Arrange T-spot test if possible 2) Arrange tuberculin skin testing if T respiratory physicians 2) Send EMUs x3 for TB culture (separate days) 3) Send sputum x3 for AFBs (separate days) 4 ) Lymph node aspirate if lymphadenopathy 5) Consider CT chest +/- bronchoalveolarlavage 6) Consider MRI brain +/- lumbar puncture spot unavailable Figure 19.10 CHAPTER 19 DMARDs and immunosuppressive drugs 575 Moderate infusion reaction (fever, shaking, itching, chest pain, hypotension) \200 \200 Previous infusion reaction with treatment Give prophylactic treatment with paracetamol 1 g and anti- histamine (e.g. piriton 4 mg) 30 min before treatment. Patient admitted with a py rexia. Stop biologic drug and screen for common infections. Stop infusion. Consider hydrocortisone 100 mg IV and possibly IM adrenaline 1 ml 1:1000. Gi ve paracetamol 1 g and anti-histamine (e.g. piriton 4 mg). Consider restarting infusion at a slower rate after 30 \200\22360 min. Surgical considerations All biologics should be discontinued 2 \200\2234 weeks before and after surgery (due to the increased risk of infection). For in \202 iximab surgery should ideally be scheduled for between infusions. The time to onset of action for rituximab is up to 6 months and routine surgery should ideally be scheduled 6 months after an infusion. Severe infusion reaction (anaphylactic hypotensive reaction \200\223 this is rare) \200 \200 \200 \200 \200 \200 Stop infusion and give IV \202 uids. Administer IM adrenaline 1 ml 1:1000. Consider IV ad renaline 1 ml 1:10 000. IV hydrocortisone 200 mg. IV chlorpheniramine 10 mg. Additional res uscitation as required. This page intentionally left blank 577 INDEX A abatacept 568 \200\22375 abdomen eye problems 48, 55, 340 gastrointestinal disease 82, 340 heart disease 66 nervous system 9 3, 95 pregnancy 368 skin disease 101 Beighton score 442 benign angiopathy of the CNS 93 ben ign joint hypermobility (BJH) 442 \200\2233 biceps 138, 146 bicipital tendinitis 143, 149 b iofeedback 482 biologics 568 \200\22375 bisphosphonates 403 \200\2234 blastomycosis 476 ble pharitis 49, 52 blind loop dermatosis-arthritis syndrome 101 blood gasses 61 body habitus 9 bone anserine bursitis 179 antalgic gait 9 anterior cruciate ligament 174 \200\2235, 181 anterio r lateral tract 121 anterior uveitis 49, 51 anti-C1q antibodies 39 \200\22340 anticardiolip in antibodies 39 anti-CD20 568 \200\22375 anticonvulsants acute surgical 88 examination 85 \200\2236 Abrams pleural biopsy 58 acalculous cholecystitis 83 accessory navicular bone 194 acetabula r labral tears 169 acetabular rim syndrome 170 Achilles tendon and bursa injections 114 Ach illes tendonopathy 192 acid maltase de \201 ciency 523 acne fulminans 101 acrodermatitis c hronica atrophicans 466, 467 acrodermatitis continua of Hallopeau 101 acromegaly 492 acromi oclavicular joint 137 inducing osteomalacia 424 pain control 481 anti-cyclic citrullinated peptide (CCP) antibodies 40 \200\2231 anti-IL-1 568 \200\22375 anti-IL-6R 568 \200\22375 anti-malarials 544 \200\2235 anti-neutro phil cytoplasmic antibodies (ANCA) 41 antinuclear antibodies (ANA) 21, 38 \200\2239 antiphospholipid antibodies 39 antiphospholip id syndrome (APLS) 274 \200\22380 injections 109 osteoarthritis 142 \200\2233 diseases 395 \200\223436 mineral density 396, 399 pain 2, 19 proliferation 25 scanning 36 \200\2237 sclerosis 434 \200\2235 tumors 528 \200\2239 actinomycetes 476 action potentials 44 active movement 9 acute cutaneous lupus erythematosu s de \201 nite 274 eye problems 48 heart disease 66, 67, 71, 276 nervous system 93, 95 pregn ancy 274, 276, 279, 367 skin disease 98 (ACLE) 98 acute renal failure 79 \200\22380 acute surgical abdomen 88 adalimumab 84, 568 \200\22375 a dductor longus injury 171 adductor pollicis longus 147 adductor tendinitis injections 113 a denosine monophosphate (myoadenylate) deaminase (AMPD) de \201 ciency 523 Borrelia burgdoferi 19, 466 Bouchard \200\231s nodes 374 brachialis 146 brachioradialis 146 , 147 bronchiectasis 55, 56, 62 bronchiolitis 55, 56, 62 bronchoalveolar lavage (BAL) 60 br onchomalacia 55 brucellosis 15, 464 \200\2235 Buergher \200\231s disease 348 \200\2239 bull horn sign 237 bullous lupus erythematosus 98 bupivacaine injections 107 bursa anti-synthetase syndrome 284 anti-TNF 71, 568 \200\22375 aortic insuf \201 ciency/regurgit ation 69 aortitis 66, 67, 68, 70, 72 apatite-like clumps 42 appendicitis 83 arterial blood gasses 59 ascending tracts 121 aseptic necrosis 381 aspiration adjunct analgesics 481 adolescents, history taking 6 \200\2237 adult onset Still \200\231s disease (AOSD) 66, 496 \200\2237 airways 54, 55, 56, 58, 59, 62 alcohol 20 alkaptonuria 516 \200\22317 allergic conjunctivitis 50 allopurinol 84, 386, 387 alpha-1 antitrypsin de \201 ciency 515 alphaviral infections 468 ALT/AST 86 amyloid 83, 88 amyloidosis 83, 498 \200\2239 anaerobic streptococcal myonecrosis 461 anakinra 568 \200\22375 analgesics 480 \200\2231 ANCA-associated vasculitis (AAV) joints 16, 106 \200\2237 oesophageal dysmotility 82, 87 atlanto-axial instability 125 atrophoderma of Pasini and Pierini 99 aurano \201 n 546 \200 \2238 aurothimalate 546 \200\2238 autoimmune connective tissue diseases 52, foot 187 knee 175 shoulder 139 ultrasound 27 239 \200\223311 bursitis 458 \200\2239 anserine 179 crystal 149 hip 168 iliopsoas 168 infrapatellar 179 int ermetatarsal 194 ischiogluteal 168 lateral pre-malleolar 191 non-septic 458 olecranon 149 p repatellar 178 \200\2239 retrocalcaneal 192 septic 149, 458 \200\2239 subcutaneous calcanea l 192 traumatic 149 trochanteric 112, 168 Buschke scleredema 99 autoimmune pancreatitis 84 \200\2235 autoimmune serology 38 \200\22341 autoin \202 ammator y syndromes 500 \200\2235 autosomal dominant hypophosphataemic rickets (ADHR) 424 avascular necrosis 168 \200\2239, 381 axillary nerve injury 144 azathiop rine 84, 552 \200\2234 general management 330 \200\2231 kidney disease 74 nervous system 94, 95 anconeus 147 ankle B back pain 130 bacterial meningitis 95 bacterial myositis 460 bacterial overgrowth 84, 88 Baker \200\231s (popliteal) cyst 181 \200\2232, 188 Bankart lesion 142 Barmah Forest virus 468 Barrett \200\231s metaplasia 82, 87 basic calcium phosphate crystals 392 \200\2233 basi lar invagination 125 Bath Ankylosing Spondylitis Functional Index anatomy 184 \200\2235 impingement syndrome 190 \200\2231 injections 114 \200\22315 regional musculoskeletal conditions 190 \200\2233 ankylosing spondylitis (AS) 214 \200\22319 anti-TNF therapy 217 chest disease 54 discriminating from DISH 216 eye problems 48 heart disease 66 HLA B27 214 measurement scale (BASFI) 4 modi \201 ed New York Criteria for C calci \201 c tendinitis, rotator cuff 141 calcium intake 397 \200\2238, 422, 423 calcium oxalate crystals 42 calcium pyrophosphate dihydrate (CPPD) (BASFI) 4 behavioral therapy 482 Beh et \200\231s disease 15, 340 \200\2231 diagnosis 214 nervous system 92, 93 crystals 42 chest disease 54 anserine bursa injections 113 INDEX 578 computed tomography (CT) 30 \200\2232 conduction system disease 66 \200\2237, 68, 69, 70 co nduction velocity (CV) 44 congenital contractural arachnodactyly 438 congenital heart block 67, 71 conjunctivitis 49 constipation 83, 88 co-prevalent conditions 3 coronary artery dis ease (CAD) 66, 67, 68, disc herniation 124 \200\2235, 131 \200\2232 discitis 126, 133, 454 \200\2235 discoid lupus erythematosus 98 disease modifying anti-rheumatic drugs calcium pyrophosphate dihydrate (CPPD) disease 14, 15, 388 \200\22390 Camurati \200\223Engelman disease 434 cANCA 41 candidiasis 82, 87 capsaicin 481 cardiac amy loid 71 cardiac nodules 71 cardiovascular disease 20, 66 \200\22372 carnitine de \201 cien cy syndrome 523 carnitine palmitoyltransferase (CPT) II (DMARDs) 531 \200\22375 distal interphalangeal joint (DIPJ) 152 distal motor latency (DML) 44 distal radio-ulna joi nt injections 111 osteoarthritis 158 DNA antibodies 39 double vision 51 Dranunculus medinensis 477 driving 96 drug history 20 drug-induced problems 70, 71 coronary ligament injections 113 costochondritis 55, 61 COX-II inhibitors 481 coxa valga 16 4 coxa vara 164 cranial setting 125 cricoarytenoiditis 55, 62 Crithidia luciliae assay 39 C rohn \200\231s disease 83, 230 cruciate ligaments 174 \200\2235, 181 cryoglobulinaema 75, 8 2, 334 \200\2235 cryopyrin-associated periodic syndrome de \201 ciency 523 carpal tunnel 152 carpal tunnel syndrome 160 \200\2231 injections 112 neurophysiology 45 gastrointestinal tract 84 lupus 20, 241, 248 \200\2239 myopathies 20, 292 \200\2233 osteoma lacia 424 pneumonitis 56, 62 side-effects of rheumatological carpometacarpal joint osteoarthritis 158 cataract 49 caudal epidural 115 cellulitis 458 cer ebrospinal \202 uid 92 cervical spine 119, 122, 124 \200\2237 chest disease 31, 54 \200 \22364 chest wall 54, 55 \200\2236, 57 \200\2238, 61, 128 \200\2239 Chikungunya virus 468 c hilblain lupus erythematosus 98 Child Health Assessment Questionnaire (CAPS) 504 \200\2235 cryptococcosis 476 crystal arthritis 15, 383 \200\22393 crystal bursit is 149 crystals, features 42 CT pulmonary angiogram (CTPA) 60 CTLA4 \200\223Ig 568 \200\223 75 cubital tunnel syndrome 151, 161 cuneate tracts 121 cutaneous calcinosis 99 cutaneous lu pus erythematosus 98, 244, 249 cutaneous vasculitis 100 cyclo-oxygenase-II (COX-II) inhibit ors 481 cyclophosphamide 84, 562 \200\2236 cyclosporin A 558 \200\22360 cysticercosis 461 c ytomegalovirus (CMV) 241 drugs 49, 94 Dupuytren \200\231s disease 162 DXA scanning 400 E echinococcus 477 echocardiography 60, 61, 69 Ehlers \200\223Danlos syndrome (EDS) 82, 440 \200\2231 elbow (CHAQ) 4 children dermatomyositis (JDM) 298 \200\223300 examination 10 \200\22311 GALS examination 11 growing pains 7 history taking 3 \200\2234, 6 \200\2237 osteoporosis 412 \200\22313 pain 2, 6 \200 \2237 rickets 422 \200\2235 torticollis 126 \200\2237 see also juvenile idiopathic arthriti s anatomy 146 \200\2237 differential diagnosis of pain 148 injections 110 nerve entrapment 15 0 \200\2231 osteoarthritis 149 \200\22350 regional musculoskeletal conditions 148 \200\2235 1 elderly, history taking 6 electrocardiogram (ECG) 61, 69 electroencephalogram (EEG) 92 el ectromyography (EMG) 22, 44 \200\2235, 92 ELISA 39 empyema 62 encephalitis 95 endocardial d isease 66 endocrine disorders 285 endosteal hyperostosis (EH) 434 enteric arthritis 83, 226 enteric spondyloarthropathy 230 enteropathic spondyloarthropathy 230 \200\2231 enthesitis 14 chloroquine 544 \200\2235 cholecystitis 89 cholesterol crystals 42 chondrocalcinosis 388 ch ondroma 529 chondrosarcoma 529 Chopart joint 187 chorea 462 choroidal neovascular membrane 51 Christmas disease 510 \200\22311 chronic kidney disease (CKD) 80 \200\2231, 426 chronic pain 479 \200\22390 Churg \200\223Strauss syndrome (CSS) 326 \200\2237 D dactylitis 195 daytime somnolence 96 De Quervain \200\231s tenosynovitis 26, 159 injections 111 debranching enzyme de \201 ciency 523 deep morphea 99 delayed gastric emptying 83, 87 delt oid 137, 138 denervation 44 \200\2235 denosumab 405 depomedrone injections 107 dermatomes 1 20 dermatomyositis (DM) 290 \200\2236 gastrointestinal disease 82 heart disease 66 nervous system 93 pregnancy 368 treatment 330 \200\2231 chylous arthritis 476 ciclosporin 84, 558 \200\22360 CINCA/NOMID 504 clavicle 136 chest wall 61 knee 178 pelvis 171 chest disease 54 eye problems 48 gastrointestinal disease 82 heart disease 66 juvenile 298 \200\223300 nervous system 93, 95 skin disease 98 \200\2239 descending tracts 121 diabetes mellitus 100, 494 diabetic cheiroarthropathy 162, 494 diabetic femoral amyotrophy 494 diabe tic foot ulcers 455 diabetic osteoarthropathy 494 diabetic osteomyelitis 455 diaphyseal acl asia 435 diarrhea 83, 88 diet enthesitis-related arthritis (ERA) 232 \200\2234, 352 eosinophilia-myalgia syndrome 520 \200\2231 eosinophilic fasciitis 310 \200\22311, 520 epis cleritis 49, 52 Epstein-Barr virus (EBV) 241 equipment, examination 8 erosions 25 erosive o steoarthritis 375, 376 erythema migrans 466, 467 erythema nodosum 514 erythroderma 102 etan ercept 84, 568 \200\22375 examination 8 \200\22312 exercise tests 61 exocrine pancreatic in suf \201 ciency 83, 88 extensor carpi radialis brevis 147 extensor carpi radialis longus 1 47 extensor carpi ulnaris 147 osteomyelitis 455 clergyman \200\231s knee 179, 458 clinical assessment 1 \200\22323 clinical neurophysiology 44 \200\2235 \200\230closed chain \200\231 9 Clostridial myonecrosis 460 \200\2231 club f oot 185 coccydynia 133 codeine 481 coeliac disease 83 Cogan \200\231s syndrome 338 \200\223 9 cognitive behavioral therapy 482 colchicine 84 colitis 83, 88, 230 collagen disorders 437 \200\22343 collateral ligaments 174, 180 \200\2231 compartment syndromes 184, 188 compleme ntary therapies 376 \200\2237, 482 complex regional pain syndrome type I gout 387 post-menopausal osteoporosis 397 \200\2238 diffuse alveolar damage (DAD) 56 diffuse cutaneous systemic sclerosis 264, 271 tenosynovitis 159 extensor digiti minimi 147, 154 extensor digitorum communis 147, 154 extensor indicis propr ius 147, 154 extensor pollicis brevis 147, 154 extensor pollicis longus 147, 154 extractabl e nuclear antigens (ENA) 39, 40 eye problems 15, 48 \200\22353 diffuse idiopathic skeletal hyperostosis (DISH) 216, 380