short, medium, long, and very long-chain acyl-CoA de- hydrogenases (VLCAD), and produce a wide spectrum of clinical phenotypes. VLCAD de \201 ciency presents similarly to CPT II de \201 ciency and may be clinically indistinguishable. Disorders of purine metabolism Adenosine monophosphate (myoadenylate) deaminase (AMPD) de \201 ciency About 1.2 \200\2233.7% of the general population are homozygous for AMPD mutati ons and de \201 ciency of AMPD has been reported in up to 3% of muscle biopsies. However, the clinical signi \201 cance of this is debatable. It has been sug- gested that AMPD de \201 ciency may result in exercise intol- erance and myalgia in a subset of affected indivi duals. Conversely, the prevalence of AMPD de \201 ciency does not appear to be increased i n patients with muscle symptoms compared with the general population. Debranching enzyme de \201 ciency \200 \200 \200 \200 May cause progressive myopathy in the 2nd to 3rd decade. Weakness and wasting is often pred ominantly distal. Respiratory muscles are occasionally involved. A mild sensory axonal poly neuropathy is frequently seen. Disorders of lipid metabolism These include: \200 \200 Carnitine de \201 ciency syndromes: muscle or systemic. Fatty acid transportation defects: carnitine palmitoyltrans- ferase II de \201 ciency is the most common. Defects of B oxida tion enzyme. Mitochondrial myopathies These are a diverse group of multisystem diseases resulting from a bnormalities of the respiratory chain. Inheritance is either maternal or Mendelian accordin g to whether genetic defects affect mitochondrial or nuclear DNA. METABOLIC MYOPATHIES 524 This test carries a risk of rhabdomyolysis and a non- ischaemic version has been advocated. Glycogenoses cause absence or blunting of the normal rise in lactate (with the exception o f acid maltase, brancher and phosphorylase b kinase de \201 ciencies). Results are normal in disorders of lipid metabolism. Lactate and pyruvate may be elevated in mitochondrial myo pathies. Muscle involvement is common but the predominant symptoms are usually extra-muscular, e.g. blindness, deaf- ness, encephalopathy, ophthalmoplegia, and seizures. There are numerous re cognized syndromes, such as MERRF (myoclonic epilepsy with ragged red \201 bres), MELAS ( mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes), and PEO (pr ogressive external ophthalmoplegia). A subset of patients may present with progressive mus- cle weakness in the absence of overt systemic manifesta- tions, and a detailed family hist ory and thorough evaluation for potential associated features is therefore required. \200 Electromyography (EMG) \200 May show myopathic features in glycogenoses, especially in patients with progressive weakne ss. Marked insertional irritability may be evident in acid maltase de \201 ciency. Often n ormal in mitochondrial disorders and between symptomatic episodes in CPT II de \201 ciency . Investigation of metabolic myopathies Investigation beyond basic blood and urine tests is g ener- ally undertaken in a specialist setting. Further tests These should be directed by the clinical presentation. \200 Laboratory General \200 Carnitine levels may be abnormal in disorders of lipid metabolism. Serum and urine analysis for fatty acid metabolites is often informative. Enzyme testing in white blood cells or sk in \201 broblasts may be useful in acid maltase de \201 ciency. Identi \201 cation of t he responsible genetic defect is now possible in many of the metabolic myopathies. FBC: haemolytic anemia can occur in some glycog- enoses. LFTs, renal pro \201 le, bone pro \201 le, LDH, urate. Rhabdomyolysis may lead to elevated creatinine, potas- sium, urate, phosphate, and reduced calcium. Serum myoglobin may be detectable in acute rhabdomy- olysis , but is cleared rapidly (within 1 \200\2236 h). \200 Differential diagnosis of myopathy Muscle pain, fatigue, and cramps are ubiquitous complain ts, and it may be dif \201 cult to determine whether an underlying pathological process is likely. However, severe, aching pain on exertion, prolonged cramps, and myoglobinuria are suggestive of metabolic muscle disease. A thorough family history and evaluation for extram uscular features are man- datory. The numerous alternative causes for muscle cramps should also be considered, including: \200 \200 \200 \200 \200 \200 Creatine kinase (CK) \200 CK should be tested at rest and during acute attacks of muscle symptoms. Glycogenoses tend to cause a persistently raised CK. Elevation is usually mild to moderate, although CK may b e very high in acid maltase de \201 ciency. In lipid oxidation defects, CK is usually norm al between episodes of rhabdomyolysis. Electrolyte abnormalities: low calcium, magnesium. Peripheral vascular disease. Hypothyroid ism, hyperparathyroidism. Drugs/toxins, e.g. diuretics, statins, alcohol. Motor neuron dise ase: leg cramps are common. Peripheral neuropathy and radiculopathy. Urine myoglobin \200 Dark urine, positive for blood on dipstick, but with no red cells/casts on microscopy may i ndicate myoglobinuria. Semi-quantitative assay for haem pigments have approxi- mately 80% s ensitivity for myoglobin. Crucially, lack of detectable urine myoglobin does not exclude rh abdomyolysis. In patients presenting with progressive muscle weakness, the differential is wide and inclu des the idiopathic in \202 am- matory myopathies, muscular dystrophies, endocrinopa- thies , and drugs. Imaging MR and CT scanning have been utilized in glycogen storage disorders to characterize muscle pathology and are useful to guide muscle biopsy. Nuclear MR spectroscopy provides a n assessment of muscle metabolism, and may be useful in detecting glycolytic and mitochondr ial defects. Treatment General management strategies include: \200 \200 Avoidance of activities that precipitate symptoms. Dietary modi \201 cation: A high protei n diet and pyridoxine supplements have been advocated for McArdle \200\231s disease; howeve r, a recent Cochrane Review concluded there was insuf \201 cient evidence to recommend any speci \201 c intervention. A low fat, high carbohydrate diet with sup- plementary intake before exercise appears useful in CPT II de \201 ciency. Carnitine, ribo \202 avin, and m edium chain triglycerides have been trialed in disorders of lipid metabolism with some succ ess. Low dose creatine supplements have been shown to be bene \201 cial in McArdle \200 \231s disease, although higher doses appeared to be detrimental. Moderate intensity exercis e program have been shown to improve symptoms in mitochondrial disorders and glycogenoses a nd are likely to be helpful in other metabolic myopathies. Histology Muscle biopsy Diagnosis often rests on speci \201 c biochemical testing of muscl e tissue for enzyme activity. However, given the large number of potential defects, this sh ould be targeted ac- cording to initial clinical evaluation. Microscopy may reveal lipid or glycogen storage vacuoles but equally may be nor- mal. Ragged red \201 bres suggest mito chondrial myopathy, but are not pathognomonic. Other Forearm ischaemic lactate test \200 Involves exercising the forearm with an inflated blood pressure cuff in situ to create anae robic condi- tions, and serial blood tests for lactate, pyruvate, CK, and ammonia. CHAPTER 18 Miscellaneous diseases 525 Novel therapeutic strategies include enzyme replacement and gene therapies. Intravenous rec ombinant acid A-gluco- sidase has been shown to have bene \201 cial effects in acid maltas e de \201 ciency. Progress towards gene therapy has been made using animal models, althoug h it remains to be seen whether this is transferable to humans. Hanisch F, Joshi P, Zierz S. AMP deaminase de \201 ciency in skeletal muscle is unlikely t o be of clinical relevance J Neurol 2008;255: 318 \200\22322. Kishnani PS, Corzo D, Nicolino M, et al. Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology. 2007; 68: 99 \200\223109. Niranjanan N, Holton J, Hanna M. Is it really myositis? A considera- tion of the differenti al diagnosis. Curr Opin Rheumatol 2004; 16: 684 \200\22391 Resources ICD-10 codes E74.0 Glycogen storage disease E75.6 Lipid storage disorder unspeci \201 ed G71.3 Mitichondrial myopathy Pierelli PL, Amabile G, Valente G, et al. Muscular cramps: proposals for a new classi \201 cation. Acta Neurol Scand 2003; 107: 176 \200\22386. Quinlivan R, Beynon RJ, Martinuzzi A. Pharmacological and nutri- tional treatment for McArdle disease (Glycogen Storage Disease type V). Cochrane Database Syst Rev. 2008; 2:CD003458. References Bonnefont JP, Djouadi F, Prip-Buus C, Gobin S, Munnich A, Bastin J. Carnitine pa lmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol Aspects Med 20 04; 25: 495 \200\223520. Vorgerd M, Zange J, Kley R, et al. Effect of high-dose creatine ther- apy on symptoms of ex ercise intolerance in McArdle disease: double-blind, placebo-controlled crossover study. Ar ch Neurol 2002; 59: 97 \200\223101. Darras BT, Friedman NR. Metabolic myopathies: a clinical approach; Winkel LP, Van den Hout JM, Kamphoven JH, et al. Enzyme replace- ment therapy in late-onset Pompe \200\231s disease: a three-year follow- up. Ann Neurol. 2004; 55: 495 \200\223502. part I. Pediatr Neurol 2000; 22(2): 87 \200\22397. Dimauro S, Lamperti C. Muscle glycogenoses. Muscle Nerve 2001; 24: 984 \200\22399. Wortmann RL. Metabolic and mitochondrial myopathies. Curr Opin DiMauro S. Muscle glycogenoses: an overview. Acta Myol 2007; Rheumatol 1999; 11(6): 462 \200\2237. XXVI: 35 \200\22341. See also Polymyositis (p. 282) Dermatomyositis (p. 290) Haller RG. Treatment of McArdle disease. Arch Neurol 2002; 57: 923 \200\2234. SYNOVIAL OSTEOCHONDROMATOSIS 526 Synovial osteochondromatosis De \201 nition Synovial osteochondromatosis is a rare condition of syn- ovium causing mult iple loose bodies with in a joint cavity. General investigations Imaging X-ray \200 There is the characteristic appearance of popcorn in the joint if the loose bodies are calc i \201 ed. Secondary OA may develop. Epidemiology \200 \200 Occurs equally in males and females. Onset is typically aged 30 \200\22350 years. MRI MRI can demonstrate the chondromata before calci \201 cation. Etiology Results from metaplasia of synovial tissue into cartilage, which can subsequently calcify or ossify. The trigger for the condition is unknown. Differential diagnosis Similar calci \201 ed loose bodies can be seen following joint trau ma, osteochondritis dessicans, tumoural calcinosis, and severe OA. Clinical features Key features on history \200 \200 Prognosis Progression is generally slow with eventual development of secondary OA. The cond ition may be self-limiting with cessation of production of new chondromata. Synovial chondr omata do not become malignant. Usually occurs in a single joint and rarely polyarticular. Most commonly affects the knee ( >50% cases) hip, shoulder, elbows, TMJ and hands. Presentation is with pain and swelling of the joint. Joint locking. \200 Pathology The synovium is hyperplastic with numerous villi. There are cartilaginous nodules within the synovium and also within the joint space. Key features on examination \200 \200 A \201 rm mass may be palpable. There is often restriction of movement, with pain and swe lling. Synovial \202 uid Non-speci \201 c in \202 ammatory changes may be seen Patient advice \200 Rare condition, for which symptomatic treatment is usu- ally adequate. Surgical removal of loose bodies may be necessary Treatment \200 \200 NSAIDs for pain relief and reduction in \202 ammation. Arthroscopy or open arthrotomy for removal of loose bodies and synovectomy. These may need to be repeated as the condition may recur. References Crotty JM, Monu JU, Pope TL. Synovial osteochondromatosis. Radiol Clin N Am 1996; 34: 327 \200\22342. Figure 18.6 Shoulder arthrography showing multiple intra- articular loose bodies typical of synovial osteochondromatosis. CHAPTER 18 Miscellaneous diseases 527 Pigmented villonodular synovitis De \201 nition Pigmented villonodular synovitis (PVNS) is a group of benign proliferative conditions of the synovium and mes- enchyme. Differential diagnosis The isolated form needs to be distinguished from other lesions such as ganglions and foreign body granulomata. PVNS as a cause of haemarthrosis needs to be distin- guished from other causes of bloody kn ee effusions, such as trauma, clotting disorders, neuropathic joints, sickle cell anemia, a nd hypermobility. Recurrent haemorrhagic effu- sions should raise the possibility of PVNS. Epidemiology \200 \200 Occurs equally in males and females. The incidence is around 2/million/year. Localized form needs to differentiated from other causes Etiology The etiology is clonal in nature and PVNS is now consid- ered to be a benign neopl asm of synovium. of joint locking, such as menisceal tears. Prognosis Progression is generally very slow; however, the diffuse form can cause signi \201 cant disability. Clinical features Key features on history There are three modes of presentation \200 Pathology Exuberant proliferation of synovial lining cells. They are invasive and form \201 nger-like extensions or villi, which \201 ll the joint space with lobulated masses t hat invade into the subsynovial connective tissue leading to bone erosions and destruction. Histologically, there are multinucleated giant cells and haemosiderin laden macrophages, g iving rise to the characteristic color of the lesion. Isolated tenosynovitis: this typically presents in the hand with a painless mass on a \201 nger adherent to a tendon. Diffuse form: the diffuse form of PVNS usually affects the knee. Presentation is a gradual onset of pain, swelling, and stiffness, affecting a single joint. Less commonly the hip, ankle, hand, shoulder, or spine are involved. Localized form: this is the least common. Presentation is with joint swelling and locking due to a free \202 oating pedunculated intra-articular mass. Patient advice \200 Benign lesion. \200 Surgery is curative in the isolated and localiz ed forms. \200 Diffuse form requires extensive removal synovium and possible joint replac ement, and may be disabling. Key features on examination \200 Isolated tenosynovitis: a painless mass adherent to a tendon. Diffuse form: warm swollen jo int with restricted range of movement. Localized form: swollen joint, which may lock Treatment \200 Isolated tenosynovitis: surgical treatment is aimed at removing the mass from the tendon sh eath and is cura- tive. Diffuse form: there are no randomized controlled trials in PVNS. Su rgery is usually synovectomy, but it is usually dif \201 cult to achieve a curative resect ion. No medical treatment is successful. Radiation synovectomy has been used in combination with extensive surgical debride- ment. In the hip and knee total synovectomy followed by t otal arthroplasty has been successful with a low recur- rence rate. Localized form: surgica l excision of the free \202 oating mass is curative. Investigation Imaging X-rays Plain radiographs do not show the lesion, but in joints with a tight capsule there may be scalloped lesions with sclerotic margins, due to local erosion or pressure from the mass. CT CT scanning shows high attenuation because of the pres- ence of haemosiderin pigment. MRI MRI is the investigation of choice. The lesion appears dark on all sequences because of the ferromagnetic nature of haemosiderin causing shortening of the T1 and T2 relaxa- tion time. The extent of the lesion can be delineated and used to plan surgery. Resources ICD-10 coding M12.2 villonodular synovitis (pigmented) References Tyler WK, Vidal AF, Williams RJ, Healey JH. Pigmented villonodular Joint aspiration Aspirated synovial \202 uid is haemorrhagic or brown in col- our, due to recurrent hemorrhage. synovitis. J Am Acad Orthop Surg 2006; 14: 376 \200\22385 BONE tumors 528 Bone tumors De \201 nition Primary tumors of bone are generally rare and comprise a spectrum from beni gn lesions to aggressively malignant lesions. Key features on history \200 Present between age 5 and 30 and is more common in men. Pain is constant, worse at night, p oorly localized, and not relieved by rest. Pain may be worsened by alcohol and relieved by aspirin. Most commonly located in the femur or tibia, but also occurs in short bones and th e spinal column. Epidemiology Generally rare conditions that can occur at any age group. Certain lesions, ho wever, have very clearly de \201 ned age- speci \201 c occurrence. Key features on examination Muscle atrophy, localized swelling, and tenderness. Classi \201 cation The World Health Organization has developed a classi \201 ca- tion sys tem for bone tumors based on histopathological criteria. General investigations Imaging \200 X-ray: small round area of osteolysis (nidus), surrounded by a halo of hyperostosis. CT sca n: shows the nidus clearly and enables surgery to be planned. Bone scintigraphy: shows an a rea of increased uptake of radioisotope. Classi \201 cation of bone tumors Bone-forming tumors \200 \200 \200 Benign: osteoma, osteoid osteoma. Intermediate: malignant osteoblastoma. Malignant: osteosa rcoma. Differential diagnosis This is from other bone tumors. When occurring close to a joint, may be mistaken for a monarthropathy. Cartilage-forming tumors \200 Benign: chondroma, osteochondroma, chondroblas- toma, chondroidmyxoid \201 broma. Maligna nt: chondrosarcoma. Pathology Cellular, highly vascular with immature bone and osteoid. Giant cell tumor (osteoclastoma) Marrow tumors (round cell tumors) \200 Treatment \200 \200 Surgical removal of the nidus. Incomplete resection may lead to recurrence. Ewing sarcoma, neuroectodermal tumor, lymphoma, myeloma Osteosarcoma Malignant tumor of bone. Characterized by formation of bone or osteoid by tumo r cells. Adapted from Dixon (2004). Key features on history Pain arising from the tumor is often not very severe, and is increa sed by activity. In the later stages lump may be palpable. Pathological fracture may occur. The course is usually quite rapid. Osteoma Slowly growing benign lesion of well-differentiated mature bone tissue. Key features on history \200 \200 \200 Usually present in between ages 20 and 40 years. Often asymptomatic. Presents with a slow g rowing hard mass. Key features on examination Localized tenderness with a palpable mass. Overlying skin may b e warm due to marked vascularity of the tumor. Key features on examination Hard, \201 rm swelling or mass. General investigations Imaging X-ray The characteristic radiological features are: \200 General investigations Imaging \200 Periosteal reaction with formation of long spicules of bone radiating perpendicular to the bone giving a \200\230sun- burst \200\231 appearance. This can also be seen in benign lesi on such as haemangioma and other malignant lesions such as Ewing \200\231s sarcoma. Codman \200\231s triangle re \202 ects elevation of the periosteum from the underlying cortex and can also occur in osteo- myelitis or Ewing \200\231s sarcoma. X-ray: dense radio-opaque well de \201 ned <3 cm in diameter. Differential diagnosis Multiple osteomata are part of Gardner \200\231s syndrome \200\223 colonic polyposis, osteomata, and soft tissue tumors. Pathology Thick trabeculae of mature bone. Treatment Excision for symptoms or cosmetic reasons. CT \200 \200 CT is useful to assess the local extent of bone. CT of the thorax should be performed at pr esentation because pulmonary metastasis is common. Osteoid osteoma Benign osteoblastic lesion, with a clearly demarcated outline. CHAPTER 18 Miscellaneous diseases 529 Multiple osteochondromata are associated with distur- bance of growth with shortness and de formity. Diagnosis is usually aged <20 years. Usually diagnosed as an incidental \201 ndi ng or presents as a painless mass. Pain is due fracture. MRI MRI is the optimum method to assess extent of the lesion in bone. \200 Differential diagnosis Osteosarcoma needs to be distinguished from other malig- nant bone t umors. Key features on examination Painless bony deformity. Pathology There is a wide spectrum of pathological appearances, but the production of osteo id or bone is essential for the diagnosis. General Investigations Imaging X-ray Plain X-rays show a bony projection with a cartilage c apped surface. Treatment Pre- and post-operative chemotherapy and surgery. Prognosis The combination of chemotherapy and surgery has im- proved survival rates to 60 \200\22370% at 5 years. Treatment Surgical resection only for symptomatic lesions. Prognosis The risk of malignant transformation to a chondrosarcoma is < 1%. The risk is muc h higher in cases of multiple osteo- chondromatosis. Chondroma Benign tumor characterized by formation of mature car- tilage. Solitary lesions a rising in the medulla (enchon- droma) Key features on history \200 Often asymptomatic. \200 When super \201 cial may become palpable as lump. \200 Pain occurs if there is a pathological fracture or malig- nant tra nsformation. Chondrosarcoma Malignant tumor characterized by formation of cartilage. Key features on history \200 \200 Pain is usually the \201 rst symptom, with a \201 rm swelling. Variable duration of sym ptoms from weeks to years. Key features on examination Palpable mass. Due to swelling of the bone. Key features on examination Firm swelling. General Investigations Imaging X-ray \200 General investigations Imaging X-rays Intra-osseous osteolytic tumor. May show thickening a nd expansion of cortex. Extension into soft tissue suggests a high-grade malignancy. Small or moderate-sized osteolytic round or ovoid areas with well-de \201 ned margins, whi ch expand and thin the cortex. Usually located in the metaphysis. MRI/CT Best method of delineating extra-osseous extent. Differential diagnosis \200 Radiologically from epidermal cysts in the terminal phalanges. Multiple enchondromata often unilateral occur in Ollier \200\231s disease. Maffucci syndrome is multiple enchondromata occurring in association with haemangiomata. Pathology Cartilage forming tumor, with pleomorphic cells. Treatment Surgical resection is required. They are relatively radio- resistant and chemothe rapeutic regimens are poorly developed. Pathology The lesion is composed of mature cartilage. Prognosis \200 \200 Treatment Surgical resection or curettage of small lesions. The 5-year survival is 50 \200\22350%. The most common site of metastasis is the lung. Prognosis Generally good, but there is a risk of malignant transforma- tion, especially in multiple enchondromatosis. References Dixon. Bone Tumors. In: Hochberg M, Silman A, Smolen J, Weinblatt M, Weisman M ( eds) Rheumatology, 3rd edn. Ottawa: Mosby 2004; 2185 \200\22399. Osteochondroma Cartilage capped bony projection on the outside surface of bone. Schajowicz F. Tumors and tumor like lesions of bone, 2nd edn. Berlin: Springer Verlag, 1994. Key features on history \200 Osteochondromata are the most common bone tumor, comprising 40% of benign tumors and 20% of all bone tumors. Most common sites are metaphysis of long bones. This page intentionally left blank 531 Chapter 19 DMARDs and immunosuppressive drugs Methotrexate 532 Sulfasalazine 538 Le \202 unomide 540 Anti-malarials (hydroxychloroquine and chloroquine) 544 Gold: intramuscular (sodium aurothimalate) and oral (aurano \201 n) 5 46 Penicillamine 550 Azathioprine 552 Mycophenolate mofetil 556 Ciclosporin (previously cyc losporin A) 558 Cyclophosphamide 562 Biologics: anti-TNF (in \202 iximab, etanercept, adal imumab), anti-CD20 (rituximab), anti-IL-1 (anakinra), CTLA4 \200\223Ig (abatacept), and ant i-IL-6R (tocilizumab) 568 METHOTREXATE 532 Methotrexate History \200 MTX is useful in psoriatic arthritis, but may not be as good as sulfasalazine. MTX is usefu l as maintenance therapy, but not induction treatment, of ANCA associated vasculitis. MTX c an be useful in SLE for the articular and cutaneous manifestations. There is no evidence to support MTX use in giant cell arteritis 1940s: aminopterin, a recently developed folic acid antagonist, being used in children with leukemia, is found to be ef \201 cacious in the treatment of patients with rheumatoid art hritis. 1950s: methotrexate (amethopterin; MTX; a less potent folic acid antagonist) is dev eloped. Weekly pulses of methotrexate are anecdotally shown to have similar ef \201 - cacy but less toxicity than aminopterin. 1960/70s: anecdotal evidence accumulates for the use o f MTX in rheumatoid arthritis and psoriatic arthritis. 1980s: double-blind placebo controll ed studies (DBPCS) con \201 rm the ef \201 cacy of weekly pulsed MTX treatment in rheumat oid arthritis and psoriatic arthritis. 1990s: folic acid supplementation is shown in DBPCS to reduce MTX toxicity and side effects but to have no effect on ef \201 cacy. MTX becomes the \201 rst choice disease modifying agent (DMARD) in rheumatoid arthritis. MTX combina tion treatments with other DMARDs is shown to be ef \201 cacious in patients not respondin g to MTX monotherapy. MTX combination treatment with other DMARDs is shown to be ef \201 c acious in early in \202 amma- tory arthritis. \200\230Inverting the pyramid \200\231 \200\223 early, rather than late treatment of rheumatoid arthritis with MTX is advocated 20 00s: MTX combination treatment with anti-TNF treatment is more ef \201 cacious than MTX mo notherapy. Rheumatoid arthritis MTX monotherapy Weinblatt ME, Coblyn JS, Fox DA (1985) Ef \201 cacy o f low- dose methotrexate in rheumatoid arthritis. N Engl J Med 312(13): 818 \200\22322. A s hort study in a small group of patients (28) in a crossover placebo controlled study showed MTX to be superior to placebo. William HJ, Willkens RF, Samuelson CO Jr, et al (1985) Comparison of low-dose oral pulse me thotrexate and placebo in the treatment of rheumatoid arthritis. A con- trolled clinical tr ial. Arthritis Rheum 28:721 \200\22330. The \201 rst large study (180 patients) showing c linical bene \201 t of MTX over placebo. Combination therapy methotrexate combines well with most other DMARDs 1. MTX, hydroxychloro quine and sulfasalazine O \200\231Dell JR, Leff R, Paulsen G, et al. (2002) Treatment of rh eumatoid arthritis with methotrexate and hydroxychlo- roquine, methotrexate and sulfasalazi ne, or a combination of the three medications: results of a two-year, random- ized, double- blind, placebo-controlled trial. Arthritis Rheum 46:1164 \200\22370. The COBRA Study: tripl e combination treat- ment with MTX, hydroxychloroquine and sulfasalazine is better than MTX and sulfasalazine in combination. MTX and hydroxychloroquine is almost as good. Possible mechanisms of action Folate antagonist MTX was developed as a folate antagonist, c ompetitively inhibiting dihydrofolate reductase. Inhibition of dihydrofo- late reductase re sults in reduced thymidine nucleotide synthesis and, therefore, reduced DNA synthesis and r e- duced lymphocyte proliferation. This is certainly its mode of action at the higher doses used in chemotherapy. Whether this is the mechanism of action in in \202 ammatory arthrit is is less clear. Methotrexate ef \201 cacy is not inhibited by folinic or folic acid co-t reatment and regular folic acid supplementation is frequently given with methotrexate. 2. MTX and le \202 unomide Kremer JM, Genovese MC, Cannon GW, et al. (2002) Con- comitant le \202 unomide therapy in patients with active rheu- matoid arthritis despite stable dose s of methotrexate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 137 (9): 726 \200\22333. Good ef \201 cacy for the combina- tion treatment, but problems with elevated liver transami- nases Adenosine release Adenosine is an endogenous anti-in \202 ammatory that is af- fected by M TX administration. Caffeine \200\223 an antagonist of adenosine \200\223 has been shown t o have inhibitory effects on the ef \201 cacy of methotrexate, in keeping with the rationa le for folate supplementation. 3. MTX and ciclosporin Tugwell P, Pincus T, Yocum D, et al. (1995) Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporin e Combination Study Group. N Engl J Med. 333(3): 137 \200\22341. T cell adhesion molecule expression In vitro studies show that MTX reduces the expression o f adhesion molecules (e.g. VCAM-1, CLA and ICAM-1) on T cells. The effects on CLA (cutaneou s lymphocyte-associ- ated antigen) may be particularly important in psoriasis. Ciclosporin with MTX is ef \201 cacious in MTX partial responders. 1. MTX and gold Lehman AJ, Esdaile JM, Klinkhoff AV, et al. (2005) A 48-week, randomized, double-blind, double-obs erver, placebo-con- trolled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis: results of the METGO study. Arthritis Rheum 52: 1360 \200\22370. Addition of IM Gold to MTX is advantageous in patients who have an inadequate response to MTX alone. Evidence base: the clinical trials with MTX and what they showed Summary There is good evid ence for MTX ef \201 cacy in rheumatoid arthritis and combination therapy should be consid ered early in the disease. MTX combines well with anti TNF treatments and most other DMARDS (except possibly sulfasalazine). CHAPTER 19 DMARDs and immunosuppressive drugs 533 2. MTX and doxycycline O \200\231Dell JR, Elliott JR, Mallek JA, et al. (2006) Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone. Arthritis Rheum 54:621 \200\2237. Treatment with doxycycline (either 40 or 200 mg p er day) and MTX in early seropositive in \202 ammatory arthritis was superior to MTX alone . ANCA associated vasculitis De Groot K, Rasmussen N, Bacon PA, et al. (2005) Ran- domized tr ial of cyclophosphamide versus methotrexate for induction of remission in early systemic an tineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 52: 2461 \200\2239 . Methotrexate is effective, but less so than cy- clophosphamide, and in patients with sign i \201 cant end organ involvement MTX should be used as maintenance treatment following re mission induction with cyclophosphamide. 3. MTX and anti-TNF Maini R, St Clair EW, Breedveld F, et al. (1999) In \202 iximab (chime ric anti-tumor necrosis factor A monoclonal anti- body) versus placebo in rheumatoid arthri tis patients re- ceiving concomitant methotrexate: a randomized phase III trial. ATTRACT St udy Group. Lancet. 354(9194): 1932 \200\2239. SLE Carneiro JR, Sato EL (1999) Double blind, randomized, pla- cebo controlled clinical tri al of methotrexate in systemic lupus erythematosus. J Rheumatol 26: 1275 \200\2239. This an d one other controlled study in SLE show ef \201 cacy for MTX for articular and cutaneous manifestations of SLE Weinblatt ME, Kremer JM, Bankhurst AD, et al. (1999) A trial of etanercept, a recombinant t umor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis rece iving methotrexate. N Engl J Med 340(4): 253 \200\2239. Prescribing considerations What do I need to do before starting the treatment? \200 Patient education with regard to dosing, side effects, monitoring, drug interactions, etc. Ensure your patient has a patient held monitoring booklet such as the one advised by the Na tional Patient Safety Agency (http://www.npsa.nhs.uk/display? contentId=5085). The two initial anti-TNF studies (with etanercept and in \202 iximab) showing that combina tion treatment with MTX and anti-TNF is ef \201 cacious in MTX non-responders Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. (2005). Clinical and radiogr aphic outcomes of four different treatment strategies in patients with early rheu- matoid a rthritis (the BeSt study): a randomized controlled trial. Arthritis Rheum 52: 3381 \200\223 90. The BeSt study showing that early combination treatment with methotrexate and anti-TNF, or methotrexate, sulfasalazine, and prednisolone, resulted in more rapid improvement clini cally and joint damage suppression than sequential monotherapy or step- up combination ther apy. Record at baseline FBC LFTs ESR or CRP Renal function Allows monitoring of changes Allows monitoring of changes Monitor disease activity Impaired renal function increases MTX levels Either history or serology Allows comparison in pulmon ary toxicity Psoriatic arthritis MTX monotherapy Willkens RF, Williams HJ, Ward JR, et al. (1984) Random - ized, double-blind, placebo controlled trial of low-dose pulse methotrexate in psoriatic arthritis. Arthritis Rheum 27: 376 \200\22381. Showed that MTX is more ef \201 cacious tha n pla- cebo \200\223 in the Cochrane systematic review of 2000 it was concluded: \200\230 The magnitude of the effect seen with \200 oral low dose methotrexate suggests that it ma y be effective, but that further multicentre clinical trials are required to establish its ef \201 cacy \200\231. Sulfasalazine and parenteral high dose MTX were seen to be more ef \201 cacious Varicella status CXR An abnormal CXR is not a contraindication to treat- ment, but the patient should be monitor ed carefully, since there is an increased risk of MTX pneumonitis in patients with pre-exis ting lung disease. Some clinicians advocate pre-treatment pulmonary func- tion to facilitat e monitoring in the event of pneumonitis (see below under pneumonitis), but this is not uni versal Liaise with the patients GP represcribing and appropri- ate monitoring of the treatm ent MTX combination therapy In psoriatic arthritis the only good evidence is for ciclospo- rin and MTX combination treatment: Fraser AD, van Kuijk AW, Westhovens R, et al. (2005) A rando mized, double blind, placebo controlled, multicentre trial of combination therapy with meth otrexate plus ciclo- sporin in patients with active psoriatic arthritis. Ann Rheum Dis 64: 859 \200\22364. Showed that patients responding inade- quately to MTX alone bene \201 ted from additional DMARD treatment with ciclosporin. What dose should I prescribe? \200 \200 \200 Oral methotrexate: 7.5 \200\22325 mg/week. Methotrexate should not be crushed or chewed. Me thotrexate is a weekly treatment, e.g. M is for Methotrexate on a Monday. Various protocols are used for dosage escalation. S ome use a more rapidly escalating regime than others. Giant cell arteritis There is no evidence for the use of methotrexate in GCA. Hoffman GS, C id MC, Hellmann DB, et al. (2002) A multi- center, randomized, double-blind, placebo-contro lled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum. 46 : 1309 \200\22318. One of several good quality studies that have failed to show any bene \201 t for MTX in giant cell arteritis. METHOTREXATE 534 Note: MTX does not appear to cause pulmonary \201 brosis Warn patients to report new: dry cough +/- dyspnoea. Example regime: \200 10 mg/week starting dose increasing at 6 weeks (if blood test monitoring satisfactory) to 1 5 mg/week. Thereafter, 3 monthly increases of 2.5 mg/week (if blood test monitoring satisfa ctory) until dose of 25 mg/week or disease adequately controlled. In vasculitis the usual s tarting dose in 15 mg/week. Hepatic toxicity \200 \200 \200 \200 MTX can cause hepatic \201 brosis and cirrhosis. More problematic in patients with psoria tic arthritis. Alcohol exacerbates this problem. Warn patients to avoid alcohol (psoriatic) and to minimize alcohol (rheumatoid). Oral versus parenteral treatment \200 Above 20 mg/week the bioavailability of oral meth- otrexate is variable and partial respond ers may ben- e \201 t from a change to parenteral (usually subcutaneous) treatment Overall dose should be adjusted on conversion due to improved bioavailability 20 mg/week of oral M TX = 15 mg/week of SC. MTX FAQs How long does it take to work? A clinical response is usually seen after 3 months of treat- ment with methotrexate What if I want to get pregnant? Methotrexate is teratogenic, and should be avoided before and during pregnancy. It can have effects on both sperm and ova. It can also cause miscarriage. Methotrexate should be disco ntinued at least 3 months prior to planned con- ception by men and women Folic acid prescription? \200 Folic acid supplementation reduces side effects (muco- cutaneous and hepatic) without affec ting ef \201 cacy and is generally prescribed routinely. It should not be given the same d ay and is usually given weekly like MTX, e.g. F for Folic Acid on a Friday What about fertility? Methotrexate may affect fertility in both and men and women although this has not been exte nsively studied. What about injections? \200 Important drug interactions \200 Live attenuated vaccines need to be avoided by patients taking methotrexate: yellow fever, MMR and rubella, BCG, oral polio, oral typhoid. Other vaccines will not be a problem. Patie nts should be advised to have an annual in \202 uenza immunization since they are at an in creased risk of in \202 u- enza. Trimethoprim and Cotrimoxazole (Septrin) can cause acute pancytopenia and should be avoided . Phenytoin can increase the anti-folate effects of MTX. Probenecid decreases MTX excretion . NSAIDs do not signi \201 cantly interfere with MTX at the doses used rheumatologically \200 \200 \200 What if I miss a dose? Methotrexate can be taken at the normal dose up to 48 h after the us ual time of the weekly dose. If later than 48 h the dose for that week should be omitted an d the normal dose taken the following week. Monitoring \200 FBC & LFTs: the British National Formulary advises weekly until therapy is stabilized and t hereafter 2 \200\2233 monthly. ESR: useful for monitoring response to treatment Can I drink alcohol? Patients with psoriatic arthritis should be advised to avoid alcohol. Patients with rheumatoid arthritis should be ad- vised to minimize alcohol consumption Side effects and what to discuss with your patients Common Nausea, abdominal discomfort, di arrhea, anorexia, oral ulceration. What to do if side effects occur Common side effects \200 \200 Hematological toxicity Neutropenia, thrombocytopenia, pancytopenia. Warn patients to report infections/sore throat/bruising Reduce the dose of MTX. Consider increasing folic acid dose. Pulmonary toxicity \200 \200 Acute interstitial pneumonitis (an acute presentation). This is a hypersensitivity reaction to methotrexate. CHAPTER 19 DMARDs and immunosuppressive drugs 535 ASYMPTOMATIC PATIENT SYMPTOMATIC PATIENT Persistent Neutropenia (<1.5x109/L) or Thrombocytopenia (<150x109/L) Neutropenia (<1.5x109/L) or Thrombocytopenia (<150x109/L) Stop MTX Give appropriate antibiotics for neutropenic sepsis Give folinic acid rescue (calc ium folinate) (IV bolus 30mg followed by 15mg qds orally x2/7) Monitor response Consider G- CSF if recalcitrant Stop MTX and monitor response Persists Resolved Persists Patient improves Consider Retreatment at Lower dose Assessment with Hematologist Consider Retreatment at Lower dose Assessment with Hematologist Figure 19.1 Hematological toxicity. Acute Respiratory Illness (Dry Cough +/-dyspnoea and fever)