Contents
1 Introduction 185 2 NSAIDs 185 3 Glucocorticoids 186 4 Conventional DMARDS 186
Sulfasalazine 186 Methotrexate 186
Oral and Parenteral Gold 187 Leflunomide 187
Azathioprine and 6-Mercaptopurine 187 Cyclosporine A 188
Antimalarial Agents 188
D-Penicillamine 188 Colchicine 188
Mycophenolate Mofetil 189 Retinoids 189
Photochemotherapy 189 Somatostatin 189 Miscellaneous 189 5 Conclusion 190
References 190
1 Introduction
Ideal therapy for psoriatic arthritis (PsA) should target both rash and joint disease in- cluding peripheral and axial presentations, dac- tylitis, and enthesitis. The significant impact of PsA on quality of life is increasingly evident and comparable in severity to that of rheuma- toid arthritis [1, 2]. Therefore, essential aims of therapy must include not only symptomatic improvement but also treatment directed at potential disease modification/amelioration.
However, traditional disease modifying anti-
rheumatic drug (DMARD) therapy, as detailed below, has been poorly studied in PsA. Uncon- trolled experience has suggested modest effica- cy for some DMARDs but these observations are especially difficult to interpret given the consistently high placebo response rates (three times as high as in RA) present in controlled PsA trials. Few well-designed, adequately-con- trolled randomized trials with traditional DMARDs have been performed, and the overall efficacy observed to date has been disappoint- ing. Problematic trial design such as the diffi- culty in defining different disease PsA sub- groups and the uncertain distribution of these subgroups between placebo and treatment arms additionally complicates the extrapola- tion of available data to clinical decision-mak- ing for the individual patient (see Chap. IV.B.
for a discussion of disease subgroups in PsA).
The latest advances in therapy for PsA appear promising and will be detailed in Chap. X.B.2;
the important development of more reliable outcome measures incorporating symptomatic, functional, and radiologic end points are de- scribed in Chap. VI.B.
2 NSAIDs
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed as the initial therapy for both peripheral and axial disease. Placebo- controlled studies assessing efficacy are limited but confirm NSAID superiority in reducing tender/swollen joint counts and pain scores. No beneficial effect on rash (assessed by PASI score) or on ESR has been demonstrated to sug- gest that NSAIDs have a disease modifying ef- fect [3]. Worsening of skin disease with initia- tion of NSAID therapy has been observed for both non-specific and COX2-specific NSAIDs [4–6], perhaps due to shunting of arachidonic acid metabolites down the leukotriene path- way; however, other controlled studies suggest this is not a major clinical issue [3]. No unusual toxicity associated with the use of NSAIDs in PsA has been reported.
B Psoriatic Arthritis
Christopher G. Jackson, Daniel O. Clegg
3 Glucocorticoids
Periodic intra-articular injection of corticos- teroid can be of particular value in patients with oligoarticular disease or those having well-controlled polyarticular disease except for one or two persistently active joints. In recent- ly-devised guidelines, two failed injections are considered sufficient evidence of aggressive disease as to warrant consideration of anti-TNF therapy [7]. In general, systemic use of gluco- corticoids should be used judiciously because of the risk of provoking a pustular flare in the skin disease on withdrawal [8].
4 Conventional DMARDS Sulfasalazine
The efficacy of sulfasalazine in RA and other seronegative arthritides led to its initial use in PsA. Benefit was suggested in a number of pilot studies, and several early controlled trials doc- umented a modest degree of clinical improve- ment. Typical of these early controlled trials [9]
is a 24-week double-blind placebo-controlled study of 30 patients using a dose of 2 g/day. Sig- nificant improvement was observed in morn- ing stiffness, number of painful joints, articular index, clinical score, and pain score, with the fa- vorable response being more pronounced in patients with polyarticular disease [10]. Clini- cal benefit was observed as early as 4 weeks in one study [11] and was associated with a reduc- tion in ESR in another [12].
Three further trials involving considerably larger numbers of patients reached similar con- clusions, with efficacy being primarily ob- served in patient-reported measures. A study of 91 patients treated with a dose of 3 g/day over 24 weeks revealed significant improvement in patient global assessment [13] whereas a study of 120 patients treated for a similar period dem- onstrated significant improvement only in re- duction of pain [14]. In the largest and longest controlled trial, which evaluated 221 patients treated with 2 g/day over 36 weeks, patient glo- bal assessment was the only efficacy parameter
to achieve statistically significant improvement [15]. Benefit with sulfasalazine appears to be confined to peripheral PsA as no improvement in axial disease has been demonstrated [16].
Only rare reports exist of either improvement or exacerbation in cutaneous disease activity with sulfasalazine therapy.
Methotrexate
The efficacy of methotrexate in PsA was first demonstrated in 1964 in a double-blind place- bo-controlled study of 21 patients with active skin disease and peripheral arthritis [17]. Three doses of parenteral methotrexate (1–3 mg/kg) were administered at 10-day intervals and pa- tients followed for approximately 3 months. Sig- nificant improvement in joint tenderness, joint range of motion, extent of skin involvement, and erythrocyte sedimentation rate was docu- mented, but the majority of patients experi- enced a recurrence of skin and joint disease within 1–4 months following therapy. Adverse events were not infrequent but were not judged severe enough to interrupt treatment.
A subsequent randomized, double-blind, placebo-controlled trial with methotrexate ad- ministered in an oral low-dose pulse regimen (7.5–15 mg/week) over 12 weeks showed better patient tolerance. However, the only response measure to attain statistical significance was the physician assessment of arthritis activity [18]. In a retrospective report of 40 patients treated over 12 years with a mean methotrexate dose of 11.2 mg/week, 38 patients had an excel- lent or good articular response, 36 had cutane- ous resolution, and only two withdrew due to toxicity (leukopenia and stomatitis) [19]. Seven patients underwent 11 liver biopsies during the study period, with one patient found to have micronodular cirrhosis at a cumulative me- thotrexate dose of 400 mg (with an unchanged biopsy at a cumulative dose of 1080 mg).
Whether the use of methotrexate in PsA pa- tients results in more frequent or severe toxicity compared with RA patients remains uncertain but no increase in adverse events was suggested in a retrospective study of 104 patients followed over 2 decades [20]. No consensus exists as to
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the indications for liver biopsy in methotrex- ate-treated PsA patients. In a 24-month study of 38 patients, no improvement in radiographic progression was seen with methotrexate com- pared to matched controls [21].
Oral and Parenteral Gold
Improvement in some clinical parameters has been observed following treatment with both oral and parenteral gold in PsA. In a 6-month double-blind placebo-controlled study of au- ranofin (6 mg/day) involving 238 patients, the auranofin-treated group showed modest but significant improvement in physician’s global assessment as well as in occupational and daily function scores compared with the placebo group. No significant difference was seen in either morning stiffness or joint tenderness/
swelling [22]. The rate of withdrawal from auranofin due to adverse drug reactions was 10%.
An uncontrolled study of parenteral gold re- ported remission or 50% reduction in number of inflamed joints in 10 of 14 patients [23] with toxicity similar to that observed in RA. A dou- ble-blind comparison of auranofin (6 mg/day), intramuscular gold sodium thiomalate (50 mg/
week), and placebo demonstrated significant improvement in the Ritchie articular index, the visual analog pain score, and the erythrocyte sedimentation rate (ESR) over 24 weeks for the parenteral gold group while the auranofin group was comparable to placebo [24]. No im- provement in radiographic disease progression was seen in a small controlled 2-year study of parenteral gold. Neither oral nor parenteral gold has been associated with significant flare or improvement in cutaneous psoriasis.
When comparisons have been made retro- spectively [25] and prospectively [26] between gold and methotrexate therapy, PsA patients treated with methotrexate appear to be 9 times more likely to respond and 5 times less likely to discontinue therapy compared to gold-treated patients. The observed mean treatment survi- val with methotrexate was 16 months compared to 6 months with gold therapy.
Leflunomide
Leflunomide is a selective pyrimidine synthesis inhibitor that targets activated T cells unable to rely solely on a salvage pathway for expansion [27]. An open-label study of six patients with psoriatic polyarthritis showed a significant de- crease in CRP level as well as in the tender and swollen joint count but not in the extent of pso- riasis after 3 months of therapy [28]. Another study conducted in 12 patients with polyarticu- lar PsA who had failed at least one DMARD confirmed the clinical efficacy of leflunomide in the 8 patients available for follow-up after 2 years [29]. Psoriatic rash improved in two- thirds of the patients.
These promising results led to a randomized double blind placebo controlled study of 6 months duration in 188 patients with active psoriatic arthritis (>3 tender and swollen joints) and active rash (>3% body surface area).
More than half of the patients had been inade- quately controlled by prior DMARD therapy in- cluding methotrexate. Fifty-nine percent (59%) of leflunomide treated patients met the pri- mary efficacy endpoint (psoriatic arthritis re- sponse criteria; PsARC) compared with 29.7%
of placebo treated patients.Additionally, 24% of leflunomide-treated patients (compared with 0% placebo-treated) had significant PASI score improvements. Treatment was relatively well tolerated with adverse effects similar to the RA experience and no unusual toxicity was report- ed [30]. Leflunomide is a teratogen and should be used with care in women of childbearing po- tential.
Azathioprine and 6-Mercaptopurine Reports of benefit with the purine analog, aza- thioprine, and its derivative, 6-mercaptopurine, exist for both psoriasis and PsA; however, the study populations are small and no placebo- controlled data are available. Eleven of 13 pa- tients treated with 6-mercaptopurine (20–50 mg/
kg per day) showed improvement in both joint and skin disease within 3 weeks of initiation of
therapy, with maintenance of this improvement on a dose of 1 mg/kg per day which produced only minimal adverse effects [31]. A 12-month double-blind crossover study of azathioprine (3 mg/kg per day) in six patients demonstrated moderate or marked joint improvement in all six patients with cutaneous improvement in four but patient tolerance was poor with the dose of azathioprine having to be reduced in five patients because of leukopenia.
Cyclosporine A
Cyclosporine A has been reported to be of pos- sible benefit in both cutaneous psoriasis and PsA. A small 6-month open study of PsA pa- tients (seven of whom were refractory to me- thotrexate) treated with a starting dose of 3.5 mg/kg per day produced marked improve- ment in joint and skin disease in seven of eight patients after 2 months [32]. There was one withdrawal from the study because of lack of efficacy, while three patients required a 25% re- duction in the cyclosporine A dose due to a 50%
increase in serum creatinine. A prospective controlled trial comparing cyclosporine A (3 mg/kg per day) with methotrexate (7.5 mg weekly) over a 1-year period reported equiva- lent efficacy in 35 patients but combined with- drawals due lack of efficacy and toxicity were greater in the cyclosporine A group [33].
A single 6-month pilot trial of cyclosporine A (3–5 mg/kg per day) in combination with me- thotrexate (10–15 mg/week) in eight patients who had failed prior second-line therapy dem- onstrated significant improvement in all pa- tients during the first month of therapy and persistent benefit for five throughout the study period [34]. Further studies are needed to de- fine the benefit and toxicity of combination therapy in PsA.
Antimalarial Agents
Chloroquine (250 mg/day) and hydroxychloro- quine (200–400 mg/day) appear to produce some clinical benefit in approximately 75% of PsA patients who have been studied but may be
associated with a significant adverse effect on the skin disease. The spectrum of suspected cu- taneous toxicity includes exacerbation of plaques, photosensitivity, generalized erythro- derma, evolution to pustular psoriasis, and/or the development of an exfoliative dermatitis.
The reported incidence of these reactions has ranged from 0% to 100%. It is important to note that more frequent reactions were observed in early trials that had fewer patients and primar- ily utilized regimens with quinacrine, while much less toxicity has been seen in more recent trials involving larger numbers of patients treated with chloroquine or hydroxychloro- quine [35].
D-Penicillamine
A favorable effect on psoriatic arthritis has been observed with the use ofD-penicillamine, but the available information is anecdotal and very limited. Eleven patients (two with spondy- litis, four with asymmetric oligoarthritis, and five with symmetric polyarthritis) were ran- domized to an initial phase consisting of treat- ment with either D-penicillamine or placebo for 4 months [36], followed by 4 months of treatment with D-penicillamine for all patients.
The maximum dose of D-penicillamine was 750 mg/ day, and no unusual toxicity was ob- served. Clinical benefit was seen only during
D-penicillamine treatment; however, no effica- cy measure attained statistically significant im- provement.
Colchicine
Colchicine is an alkaloid known to attenuate in- flammatory activity by interfering with neu- trophil chemotaxis. A pilot study reported that 11 of 22 patients with psoriasis treated with col- chicine (0.02 mg/kg/day) had significant cuta- neous clearing with four of eight patients with arthralgias being symptomatically improved [37]. A subsequent 16-week, double-blind place- bo-controlled crossover study of 15 PsA pa- tients treated with colchicine 1.5 mg/day dem- onstrated efficacy in 10 of the 12 patients (83%)
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[38]. Statistical improvement was seen in grip strength, Ritchie index, joint pain, joint swell- ing, and patient global assessment with colchi- cine treatment. Gastrointestinal symptoms re- quired the withdrawal of two patients from the study and a temporary dose reduction in five other patients. No unanticipated clinical or la- boratory toxicity was seen.
Mycophenolate Mofetil
Mycophenolate mofetil reversibly inhibits the de novo pathway of purine synthesis, resulting in suppression of B and T lymphocyte activa- tion [39]. The primary use of mycophenolate mofetil at present is in organ transplantation, although a preliminary investigation in RA has suggested benefit [40]. A potential role in PsA has also been suggested from an open trial in which three of six patients with refractory dis- ease experienced significant improvement [41].
No corresponding improvement in skin disease was seen. There were no withdrawals due to toxicity, and no serious adverse reactions were reported. Further study will be needed to con- firm and extend these preliminary observa- tions of benefit.
Retinoids
Etretinate, a vitamin A derivative, is the most commonly used retinoid in the treatment of psoriasis, and limited experience with this agent in PsA has suggested a beneficial effect.
In a pilot study of 40 patients treated with etret- inate (50 mg/day) for a mean of 21.9 weeks, sig- nificant improvement in the number of tender joints, the duration of morning stiffness, and the erythrocyte sedimentation rate was ob- served [42] with maximal improvement for most efficacy measurements observed at 12–16 weeks. Mucocutaneous reactions consist- ing of dried and cracked lips, mouth soreness, and nosebleeds were common (39 of 40 pa- tients) and required cessation of treatment in nine patients. Other relatively frequent adverse effects were alopecia, hyperlipidemia, myalgias, and elevated transaminase levels. Etretinate is a
teratogen and should not be used in women of child-bearing potential.
Photochemotherapy
The most commonly used form of photochem- otherapy involves the oral administration of 8-methoxypsoralen followed by exposure to long-wave ultraviolet-A light (PUVA). A pros- pective study of 27 patients treated with PUVA found a favorable response in 49% of patients with peripheral arthritis whereas no benefit was seen in patients with spondylitis [43]. In re- sponders, improvement in the peripheral ar- thritis seemed to correlate with clearing of the skin disease, but no such relationship was ob- served in patients with axial disease. Extracor- poreal photochemotherapy, also known as pho- topheresis, is associated with a decrease in the in vitro viability, proliferation, and mitogen re- sponse of lymphocytes but clinical improve- ment in arthritis symptoms is variable and no improvement in skin disease has been observed [44, 45].
Somatostatin
Somatostatin may benefit some PsA patients but requires prolonged intravenous infusion (48 h) and is poorly tolerated because of nau- sea. In one study, patients having more exten- sive skin lesions and polyarticular joint disease appeared more responsive [46].
Miscellaneous
Very preliminary reports of benefit in patients with PsA exist, mostly in the form of case re- ports, for a number of other therapies with agents have immunomodulating therapies common to traditional DMARDs. Excluding the cytokine inhibitors and other biologic ther- apies which are discussed in Chap. X.B, these include bromocriptine, cimetidine, fumaric acid, 2-chlorodeoxyadenosine, parenteral ni- trogen mustard, peptide T, radiation synovecto- my with yttrium-90, dietary supplements, total
lymph node irradiation, and autologous stem cell transplantation. Further study is needed to define what role, if any, these regimens might have in patient management.
5 Conclusion
For a disease as prevalent as PsA, the evi- dence base supporting the efficacy of tradi- tional DMARDs is very limited. Marginal benefit with sulfasalazine and, perhaps, gold has been demonstrated for peripheral PsA but the rationale for methotrexate and cyclo- sporin remains largely empiric despite their common use and established efficacy in cu- taneous disease. No traditional DMARD has been shown to prevent radiographic pro- gression nor has any significant impact on dactylitis, enthesitis, or axial disease been evident. Renewed interest in PsA clinical re- search has highlighted the need for better definition, standardization and validation of disease-specific outcome measures. With improved methodology, more rigorous clini- cal investigation will be possible to better define the proper place of conventional DMARDs in the treatment of PsA, whether as monotherapy, in combination with each other, or with newer biologic agents.
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