It's unclear whether disease-modifying antirheumatic agents (DMARDs) as first-line therapy in nonrheumatoid rheumatologic diseases are effective because the question has not been studied. As second-line therapy, the use of some DMARDs appears to be beneficial for patients with psoriatic arthritis (strength of recommendation [SOR: A, based on systematic reviews of good- quality randomized controlled trials) and ankylosing spondylitis (SOR: B, based on systematic reviews of moderate quality trials). Data on the safety and efficacy of DMARDs as second-line therapy for other arthritic conditions is limited (SOR: C, based on small prospective cohort trials)

Goodemote, Patricia

Jamieson, Barbara

University of Missouri: MOspace

	 vol	56,	No	11	/	November	2007	 933www.jfponline.comCliniCal INquIrIes From the Family Physicians Inquiries Network  Are DMARDs effective  for rheumatologic diseases  besides rheumatoid arthritis?Patricia Goodemote, MD Eglin Air Force Base Family Medicine Residency, Eglin Air Force Base, FlaBarbara Jamieson, MlSMedical College of Wisconsin, MilwaukeeIt’s	unclear	whether	disease-modifying	antirheumatic	agents	(DmArDs)	as	first-line	therapy	in	nonrheumatoid	rheumatologic	diseases	are	effective	because	the	question	has	not	been	studied.	As	second-line	therapy,	the	use	of	some	DmArDs	appears	to	be	beneficial	for	patients	with	psoriatic	arthritis	(strength	of	recommendation	[sor]:	A,	based	on	systematic	reviews	of	good-quality	randomized	controlled	trials)	and	ankylosing	spondylitis	(sor:	B,	based	on	systematic	reviews	of	moderate	quality	trials).	Data	on	the	safety	and	efficacy	of	DmArDs	as	second-line	therapy	for	other	arthritic	conditions	is	limited	(sor:	C,	based	on	small	prospective	cohort	trials).There are many options,  but remember the risksTraditionally,	nonsteroidal	anti-inflammatory	agents	(NsAIDs)	have	been	the	mainstay	of	treatment	for	rheumatologic	disorders	other	than	rheumatoid	arthritis.	methotrexate	has	been	used	in	psoriatic	arthritis	because	it	also	controls	the	skin	disorder;	sulfasalazine	has	been	used	in	arthritis	associated	with	inflammatory	bowel	disease,	as	it	helps	the	bowel	disorder	itself.	However,	little	evidence	shows	a	definitive	benefit	for	the	arthritis.		 The	advent	of	tumor	necrosis	factor	(TNF)	blockers	has	changed	the	direction	of	research	in	this	area;	these	agents	are	being	used	more	and	more	in	inflammatory	arthritides.	While	staying	up	to	date	on	the	TNF	antagonists,	it’s	important	to	remember	the	complications	associated	with	them—particularly	the	increased	risk	of	infections	and	increased	propensity	for	neoplastic	disorders.	Consider	those	on	TNF	blockers	as	relatively	immunosuppressed	(number	needed	to	harm	[NNH]=59	for	infection	and	154	for	malignancy).1 Richard Hoffman, MDChesterfield	Family	medicine	residency,	richmond,	vaz 	Evidence summaryThe use of DMARDs has become stan-dard of care for rheumatoid arthritis, for both therapy and prevention of progres-sion of this debilitating disease. How-ever, the use of DMARDs in nonrheu-matoid rheumatologic disease is still un-der investigation, and at this point, the use of DMARDs as first-line therapy is not recommended; however, second-line therapy with DMARDs is common.For psoriatic arthritis, DMARDs are beneficial as a second-line therapyA Cochrane systematic review identified 13 randomized controlled trials enrolling Clinical commentaryEvidence-based answer Psoriatic arthritis affecting  the joints and nailsfast trackAs second-line therapy, some DMARDs benefit patients with  psoriatic arthritis and ankylosing  spondylitisfast track934 vol	56,	No	11	/	November	2007		ThE JournAl of fAmily PrACTiCECliniCal INquIrIesa combined 1022 patients with psoriatic arthritis randomly assigned to receive a DMARD—methotrexate, sulfasala-zine (Azulfidine), azathioprine (Imuran/ Azasan), or etretinate (Tegison; no lon-ger available in the US)—compared with placebo.2 All agents were better than pla-cebo; however, only 2 agents (parenteral high-dose methotrexate and sulfasala-zine) had clinically important benefits for more than half the patients. The studies were too small to establish toxicity or to evaluate the other agents. nSAiDs are still the preferred first-line therapy, concluded a recent publication on the treatment of psoriatic arthritis, which looked at 54 different studies; however, second-line therapy could include metho-trexate, sulfasalazine, etanercept (Enbrel), infliximab (Remicade), cyclosporine, or combination therapy.3 Sulfasalazine appeared to be clinically beneficial for peripheral psoriatic arthritis. Etanercept vs placebo. An initial study (60 patients) of etanercept vs pla-cebo among patients who were permit-ted to stay on methotrexate or predni-sone showed a response rate of 87% vs 23% (P<.0001; number needed to treat [NNT]=1.56).4 infliximab vs placebo. A study of infliximab vs placebo involving 104 patients had similar results, with good response in 65% vs 10% (NNT=1.81) at 16 weeks; infliximab also inhibited radiographic progression by 22%.5 Cyclosporine. Although it is effective, reserve cyclosporine for patients who do not improve on other regimens, because of its nephrotoxicity.3 DMARDs show some benefit  in treating ankylosing spondylitisTwo recent Cochrane systematic reviews on ankylosing spondylitis examined the use of sulfasalazine and methotrexate as second-line agents.6,7 Eleven trials were included in the sulfasalazine analysis, with a total of 895 patients. Sulfasalazine demonstrated some benefit in reducing erythrocyte sedimentation rates (ESRs) and morning stiffness, but there was no evidence that the drug reduced pain or improved physical function, spinal mobility, or rate of enthesitis. Sulfasala-zine was well tolerated and may be use-ful in early mild disease for patients with peripheral arthritis and high ESRs. On the other hand, evidence was insuf-ficient to determine whether methotrex-ate benefited patients with ankylosing spondylitis. in other trials, infliximab and etaner-cept showed good potential for benefit in treating ankylosing spondylitis. One study of infliximab vs placebo showed 61.2% vs 19.2% patients with good clinical benefit at 24 weeks and only mild or moderate adverse events (P<.001; NNT=2.38).8 Similarly, a smaller study (84 pa-tients) showed that 60% of patients on etanercept vs 20% on placebo had good clinical benefit at only 12 weeks (P<.001, NNT=2.5).9 For other rheumatic diseases, studies are mixedDue to cyclosporine’s toxicity, less toxic DMARDs are being evaluated to replace it for treatment of other rheumatic dis-eases. A recent randomized controlled trial of 100 patients with antineutrophil cyto-plasmic antibody–associated systemic vas-culitis showed methotrexate may be able to replace cyclosporine for both induction of remission (methotrexate=89.8% vs cy-closporine=93.5%; P=.041) and mainte-nance of remission (69.5% vs 46.5% at 18 months; P=.023).10 Initial trials on other rheumatic dis-eases have been small and have had var-ied results. There are mixed studies on the effectiveness of adding methotrexate to corticosteroids for giant cell arteritis.11,12 There has been no evidence of effi-cacy for the new TNF antagonists in ei-ther a small study on Sjögren’s syndrome (n=14)13 or a larger study on Wegener’s granulomatosis (n=180).14 The studies for use of DMARDs in lu-pus or scleroderma are of limited quality.A review of 54 studies found NSAIDs are still the preferred first-line therapy for psoriatic arthritisCoNT INueDfast trackwww.jfponline.com 	 vol	56,	No	11	/	November	2007	 937Recommendations from othersThe Italian Society for Rheumatology consensus guidelines recommends TNF antagonists be considered in active pso-riatic arthritis resistant to (a) NSAIDs, (b) at least 2 local steroid injections, and (c) at least 2 conventional DMARDs for patients with peripheral arthritis or enthesitis. They also recommend TNF antagonists be considered for psoriatic spondylitis resistant to NSAIDs.15The Assessment in Ankylosing Spon-dylitis (ASAS) International Working Group and the European League Against Rheumatism (EULAR) recommendations for the treatment of ankylosing spondyli-tis, based on a systematic review of the lit-erature and expert opinion, indicate that: •  There is good evidence for using NSAIDs and COX-2 inhibitors for symptomatic treatment.•  Conventional DMARDs are not well supported. •  TNF antagonists show a large ben-efit in both pain and function. The ASAS/EULAR recommendation indicate that there is no evidence that any of these treatments actually modify the disease progression.16  nAcknowledgmentsThe	 opinions	 and	 assertions	 contained	 herein	 are	 the	private	 views	 of	 the	 authors	 and	 not	 to	 be	 construed	as	official,	or	as	reflecting	the	views	of	the	us	Air	Force	medical	service	or	the	us	Air	Force	at	large.references	 1.	 	bongartz	T,	sutton	AJ,	sweeting	mJ,	et	al.	Anti-TNF	 antibody	 therapy	 in	 rheumatoid	 arthritis	and	 the	 risk	 of	 serious	 infections	 and	malignan-cies:	systematic	review	and	meta-analysis	of	rare	harmful	 effects	 in	 randomized	 controlled	 trials.	JAMA	2006;	295:2275–2285.	 2.	 	Jones	 G,	 Crotty	 m,	 brooks	 P.	 Interventions	 for	treating	 psoriatic	 arthritis.	 Cochrane Database Syst Rev 2000	(3):CD000212.		 3.	 	manadan	 Am,	 sequeira	W,	 block	 JA.	 The	 treat-ment	of	psoriatic	arthritis.	Am J Ther 2006;	13:72–79.	 4.	 	mease	PJ,	Goffe	bs,	metz	J,	et	al.	etanercept	in	the	treatment	of	psoriatic	arthritis	and	psoriasis:	a	randomized	trial.	Lancet 2000,	356:385–390.	 5.	 	Kavanaugh	A,	Antoni	Ce,	Gladman,	D,	et	al.	The	Infliximab	 multinational	 Psoriatic	 Arthritis	 Con-trolled	Trial	(ImPACT):	result	of	radiographic	analy-ses	after	1	year.	Ann Rheum Dis	2006,	65:1038–1043.	 6.	 	Chen	J,	liu	C.	sulfasalazine	for	ankylosing	spon-dylitis.	 Cochrane Database Syst Rev	 2005;	 (2):CD004800.		 7.	 	Chen	J,	liu	C,	lin	J.	methotrexate	for	ankylosing	spondylitis.	 Cochrane Database Syst Rev	 2006;	(4):CD004524.		 8.	 	Heijde	D,	Dijkmans	b,	Geusens	P,	et	al.	efficacy	and	safety	of	infliximab	in	patients	with	ankylosing	spondylitis.	Arthritis Rheum	2005;	52:582–591.		 9.	 	Calin	A,	Dijkmans	bA,	emery	P,	et	al.	outcomes	of	a	multicentre	randomized	clinical	 trial	of	etan-ercept	to	treat	ankylosing	spondylitis.	Ann Rheum Dis	2004;	63:1594–1600.		10.	 	Grout	K,	rasmussen	N,	bacon	P,	et	al.	random-ized	trial	of	cyclophosphamide	versus	methotrex-ate	 for	 induction	 of	 remission	 in	 early	 systemic	antineutrophil	 cytoplasmic	 antibody-associated	vasculitis.	Arthritis Rheum	2005;	52:2461–2469.		11.	 	Jover	JA,	Hernandez-Garcia	C,	morado	IC,	et	al.	Combined	 treatment	 of	 giant-cell	 arteritis	 with	methotrexate	 and	 prednisone.	 a	 randomized,	double	 blinded,	 placebo-controlled	 trial.	Ann In-tern Med	2001;	134:106–114.		12.	 	Hoffman	Gs,	Cid	mC,	Hellmann	Db,	et	al.	A	mul-ticenter,	randomized,	double-blind,	placebo-con-trolled	trial	of	adjuvant	methotrexate	treatment	for	giant	cell	arteritis.	Arthritis Rheum	2002;	46:1309–1318.		13.	 	sankar	v,	brennan	mT,	Kok	mr,	et	al.	etanercept	in	 sjögren’s	 syndrome:	 a	 twelve-week	 random-ized,	double-blind,	placebo-controlled	pilot	clini-cal	trial.	Arthritis Rheum	2004;	50:2240–2245.	14.	 	Wegener’s	 Granulomatosis	 etanercept	 Trial	(WGeT)	 research	 Group.	 etanercept	 plus	 stan-dard	 therapy	 for	 Wegener’s	 granulomatosis.	 N Engl J Med	2005;	352:351–361.15.	 	salvarani	C,	olivieri	 I,	 Pipitone	N,	 et	 al.	recom-mendations	of	the	Italian	society	for	rheumatol-ogy	 for	 the	use	of	biologic	 (TNF-alpha	blocking)	agents	 in	the	treatment	of	psoriatic	arthritis.	Clin Exp Rheumatol 2006;	24:70–78.	16.	 	Zochling	 J,	 van	 der	 Heijde	 D,	 Dougados,	 et	 al.	Current	evidence	for	the	management	of	ankylos-ing	spondylitis:	a	systematic	 literature	 review	 for	the	AsAs/eulAr	management	recommendations	in	 ankylosing	 spondylitis.	Ann Rheum Dis	 2006;	65:442–452.	For Sjögren’s  syndrome, lupus, giant cell arteritis, and scleroderma, study results are mixed or limitedDMaRDs for rheumatolgic diseasesComing next month in Clinical Inquiriesn What are the most effective non-drug therapies for irritable bowel syndrome?n What is appropriate documentation for a patient who refuses a clearly indicated test?n How effective are steroid injections for tenosynovitis of the hand?

Are DMARDs effective for rheumatologic diseases besides rheumatoid arthritis?

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