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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 15  |  Issue : 5  |  Page : 57-63

Sulfasalzine in the management of pure axial spondyloarthritis: Need to have a relook!


1 Department of Internal Medicine, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Rheumatology, Command Hospital (SC), Pune, Maharashtra, India

Date of Web Publication23-May-2020

Correspondence Address:
Prof. Subramanian Shankar
Department of Internal Medicine, Armed Forces Medical College, Pune, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-3698.284743

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  Abstract 


The role of sulfasalazine in pure axial spondyloarthritis (axial SpA) is claimed to be almost non-existent, due to very low-quality evidence from available literature. Guidelines recommend early institution of biologic therapy if one fails 2 NSAIDs sequentially in optimal doses over 4 weeks. As NSAIDs are effective in about 70% cases, the remaining 30% patients would require biologics within the first few weeks of onset of illness. With each passing year, a significant percentage of the remaining patients would require biologics due to NSAID failure. Relapse rates after discontinuation of TNFα inhibitors at 1-year followup is almost 100%, implying lifelong therapy with biologics. Cochrane metaanalysis reveals that ASAS 40 response (40% improvement in pain, function, and inflammation) is in the range of 25%-40% for various biologics over 24 weeks. Considering that in a country with a per Capita GDP of just Rs 1.44 lakhs/ year, where 80% of people have to meet their medical expenses out of pocket and the cheapest anti TNFs cost over Rs 2 lakhs per annum, the western guidelines are clearly impractical in Indian context. In this review article, we present a contrarian view on the use of Sulfasalazine in axial SpA. We look at the available data on Sulphasalazine with a different perspective and arrive at different conclusions. We also explore the role of other innovative strategies in the management of axial SpA and suggest alternate algorithms catering to the Indian scenario.

Keywords: Axial spondyloarthritis, cost effective, innovative strategies, sulphasalazine


How to cite this article:
Shankar S, Hegde A. Sulfasalzine in the management of pure axial spondyloarthritis: Need to have a relook!. Indian J Rheumatol 2020;15, Suppl S1:57-63

How to cite this URL:
Shankar S, Hegde A. Sulfasalzine in the management of pure axial spondyloarthritis: Need to have a relook!. Indian J Rheumatol [serial online] 2020 [cited 2020 Jun 3];15, Suppl S1:57-63. Available from: http://www.indianjrheumatol.com/text.asp?2020/15/5/57/284743




  Introduction Top


The different guidelines seem very clear as to the role of sulfasalazine in axial spondyloarthritis (axial SpA).[1] There is some role in peripheral arthritis, but its role in pure axial disease is claimed to be nonexistent. It is in this background that this review article is written where we choose to take a contrarian view and highlight a different perspective. We would like to start with two case scenarios [Box 1].



The answer for scenario A seems straightforward as the guidelines clearly state that one must use some biologic therapy, preferably a tumor necrosis factor (TNF) inhibitor (anti TNF). Once we understand Mr. Sharma's financial context, the answer to Scenario B is not all that obvious. The annual cost of anti TNFs start from Rs. 2.5 lakhs (for biosimilars) and then go further up, well above the monthly income of Mr. Sharma. Clearly, biologics are out of question in scenario B as the disposable income for such a family, after catering for essential expenses, is likely to be just a couple of thousands of rupees a month.


  the Economic Context in India Top


How well off is Mr. Sharma?

India's annual per capita GDP in 2019 was USD 2040 (Approximately Rs. 12,000/month).[2] The income is skewed to the right in India; hence, the median income is closer to Rs. 8000/month.[Figure 1]a Mr. Sharma with his household income of Rs. 20,000 a month is well above the national average and is richer than 87% of Indians [Figure 1]b.[3] This data may seem surprising to most Doctors unfamiliar with economics and they might not have placed Mr. Sharma in the 87th percentile of income in India.
Figure 1: (a) Income distribution in India is right skewed. (b) The line demarcates Mr Sharma's income

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How many Indians have health insurance coverage?

As per the report of the National family health survey report of the Government of India, about 23% of men and 20% of women are covered under any kind of health scheme, either by Government or private insurers, where biologicals may be considered as an option.[4] In reality, most insurances are hesitant in covering biologics and invariably link it to hospitalization. Thus, even the 20%–23% people are effectively reduced as subcutaneous biologics are automatically excluded. Hence, almost 80% of the country (possibly 85%–90%) cannot have access to biologic agents in their algorithm, and patients often have to pay out of pocket, dipping into their wealth.

The origin of guidelines

Almost all guidelines emanate from the USA or Europe, and it is important to understand the context in which these guidelines emanate.[1],[5] While an average American earns just 30 times more than average Indian, the amount spent on their healthcare is almost 500 times higher, with over 90% covered by health insurance [Table 1]. Until one is aware of these health realities, translating Western guidelines into the Indian landscape can have disastrous consequences, and often does.
Table 1: A comparison of healthcare costs between the USA and India

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Implications of out-of-pocket expenses

A 2018 paper in BMJ showed that almost 38 million Indians were pushed below poverty line due to out-of-pocket health-care expenditure, surely some of them contributed to by well meaning Doctors who were diligently following Western guidelines in various disorders.[6]

The dilemma of managing axial spondyloarthritis

There is clearly no point in getting a good scorecard on a particular disease parameter (say reduction in pain score or assessment of spondylo arthritis international society (ASAS) 40 response) if the price to be paid involves sacrificing children education and/or selling their land/house.

It is obvious that the guidelines for treating axial SpA cannot be applied in Scenario B that represents an overwhelming 85% of the Indian population. Many rheumatologists in India, especially those who serve the middle class or the underprivileged routinely use sulfasalazine in axial SpA as they instinctively appreciate the economic reality. However, it becomes difficult for them to justify their experience when almost all guidelines seem to be conclude that sulfasalazine and other disease-modifying antirheumatic drugs (DMARDs) are ineffective in axial SpA.

We propose to have a relook at all the published literature, although with a different perspective. We will then make some Markov models, using the same data and attempt to show that sulfasalazine may still be a promising and meaningful medicine for axial SpA.


  Reviewing the Available Evidence Top


How many patients respond to nonsteroidal anti-inflammatory drugs alone?

About 70% of patients with axial SpA will respond to nonsteroidal anti-inflammatory drugs (NSAIDs).[7] The duration of therapy should ideally be in months or years, even after the patient is pain-free. However, almost 40% of rheumatologists have apprehensions about adverse effects and may refrain from continuous dosage.[8] There is also not much data to suggest if similar response rates can be expected in disease flares in subsequent years.

How effective are tumor necrosis factor blockers in axial spondyloarthritis?

Data from a recent Cochrane metaanlysis shows that ASAS 40 response (40% improvement in pain, function, and inflammation) is seen in 25%–40% of various biologics over 24 weeks.[9] Another meta-analysis of 2015, that included studies with at least 12 weeks of follow-up, showed a mean ASAS 40 response rate of 46%.[10] The ASAS 20 response in all these studies was about 65% or so. The desirable state of ASAS partial remission (value of <2 in a scale of 0–10 for pain, function, and inflammation) ranged from 10% to 16% (with one study showing 44%).[9]

Considering that the annual cost with even biosimilars (say injection adalimumab) is at least Rs. 2.5 lakhs per annum, the benefit gained can be considered modest at the best.

The relapse rate after discontinuation of TNFα inhibitors at 1 year follow-up is almost 100%.[11] The implicit implications are that these drugs need to be given lifelong.

How effective is sulfasalazine in axial spondyloarthritis?

The Cochrane review of 2014 concludes that “There is not enough evidence to support any benefit of sulfasalazine (SSZ) in reducing pain, disease activity, radiographic progression, or improving physical function and spinal mobility in the treatment of AS.”[12] A similar conclusion was arrived at in a 2005 Cochrane meta-analysis by the same authors. No new studies had been done in the interim. None of the studies had looked at the ASAS 40 response.

The literature for the efficacy of sulfasalazine in the axial disease was reviewed. The various studies compared SSZ to either placebo or to various anti-TNF agents. The data pertaining to the effect of SSZ on pure axial disease has been extracted and is summarized in [Table 2]. The level of evidence available for SSZ is low and the assessment parameters studied were quite variable. However, it is evident that by and large the efficacy of SSZ as assessed by ASAS responses is about 50%–60% of anti-TNF agents.
Table 2: Efficacy of sulfasalazine in pure axial disease

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How do anti-tumor necrosis factor compare with sulfasalazine?

Comparison of the efficacy of anti TNF agent and sulfasalazine is shown in the spider chart [Figure 2]a. It is evident that anti-TNF is almost 1.8 times as effective in achieving ASAS 20 or ASAS 40 improvement and almost 2.2 times as effective in achieving ASAS partial remission [Figure 2]a. The spider chart shows that not only is anti TNF almost 35–40 times more expensive, but it was also associated with 22 times more serious adverse effects [Figure 2]b.[9],[12] Interestingly, there were eight times more withdrawals with sulfasalazine due to minor adverse effects.
Figure 2: Spider chart comparing anti-tumor necrosis factor and sulfasalazine. (a) Comparing efficacy. (b) Comparing adverse effects and costs

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Making Markov Models

We have tried to depict the current guidelines in pictures. [Figure 3]a depicts the ideal scenario as per guidelines while 3B shows the reality in India.
Figure 3: (a) Algorithm as per ACR/EULAR guidelines, applicable among insured/affording masses in India. (Response is taken as ASAS 20). (b) Algorithm taking into consideration the economic reality in India. (c) Suggested alternate algorithm in the current scenario. (d) Ideal algorithm that needs more research

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The textbook scenario

The guidelines would expect that we should shift to a TNF blocker within 4 weeks of failing two consequent NSAIDs [Figure 3]a. Since almost 30% of patients would fail therapy, they are automatic candidates for anti-TNF. One is expected to give these drugs lifelong, and the costs would continue to increase with alternate biologics. Since SpA is characterized by disease flares, each year, a certain percentage of patients would keep getting added into the anti-TNF group so that over a few years, a vast majority of patients/almost everyone is receiving anti-TNF.

It is worthwhile looking at the cost implications of these guidelines. Even with the cheapest biosimilar (e.g. adalimumab biosimilar; approximately Rs. 2.5 lakhs per year), the cost implications are extremely high and would continue to increase over time as we shift to other biologics due to drug failure. This group would have 100% satisfaction rate.

The realistic scenario

Considering that 85% of the Indian population cannot afford anti-TNF, this leaves the rheumatologist in a dilemma as to how to proceed further [Figure 3]b. Any choice of therapy adds to the confusion as he may not be able to justify any other form of therapy. All doors except biologic therapy are closed. 15% of patients who receive anti-TNF would be satisfied with therapy. The cost implications are shown in [Table 3].
Table 3: Cost analysis of the realistic scenario of providing anti-tumor necrosis factor

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Our suggested algorithm

Our central premise is that in chronic disease, there is no hurry to gravitate toward anti-TNF agent in NSAID failures within 4 weeks. One can explore other options, as shown in [Figure 3]c, and take a few months to reach toward anti-TNF.

When we peruse the evidence, it is apparent that sulfasalazine is almost half as effective as biologics [Figure 2]a. The level of evidence is low, but the available evidence suggests a modest efficacy of the drug [Table 2]. Considering that it is almost 35 times cheaper (Rs. 7000 vs. Rs. 2.5 lakhs per annum), it offers an attractive alternative.{Table 2}

The absence of evidence is not to be treated as evidence of absence. We suggest using sulfasalazine and expect about 40% of patients to achieve ASAS 20 response. For those who fail sulfasalazine, we assess affordability to anti-TNF and come to a shared decision-making process with alternate innovative strategies for the nonaffording group.

Innovative strategies

Since almost 85% of sulfasalazine failures would not be able to afford biologics, we suggest innovative strategies. These include various options such as combination DMARDs, bisphosphonates, thalidomide, or sacroiliac joint injection.[20],[21] For those who can indeed afford anti-TNF, we go ahead with biologics. The cost-effectiveness of this strategy is given in [Table 4]. This strategy provides significantly better satisfaction rates (49% vs. 15%) at a much cheaper societal costs (Rs. 29,380 vs. Rs. 41,750) compared to the previous strategy.
Table 4: Cost analysis of our suggested algorithm

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The Direction Ahead in Spondyloarthritis Management

We do not envisage a dramatic upturn in our economy or health expenditure in the next decade or so in India. Neither do we expect the price of biologics to fall by a factor of 20–30 so as to be affordable to the common man. While biologics have indeed been the miracle drugs of rheumatology, there is a need to do further research in India on certain specific questions some of which have been enumerated [Box 2].



We envisage an ideal scenario as shown in [Figure 3]d where 5 alternative therapy states exist. In a disease that would remain lifelong, one can constantly switch between different states, based on best available evidence, but tempered judiciously with economic reality.


  Conclusion Top


What is best for the disease may not necessarily be best for the patient. Given that non pharmacological interventions (exercise, stopping smoking, weight loss, etc.) are done effectively, we wish to reiterate that there does exist some role of conventional DMARDs like sulphasalazine in predominant axial SpA. There is a need to do further research in this area to strengthen the evidence, irrespective of whichever way the evidence may turn out to be.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
van der Heijde D, Ramiro S, Landewé R, Baraliakos X, van den Bosch F, Sepriano A, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis 2017;76:978-91.  Back to cited text no. 1
    
2.
India GDP per Capita [1958 – 2019] [Data and Charts] n.d. Available from: https://www.ceicdata.com/en/indicator/india/gdp-per-capita. [Last accessed on 2019 Dec 30].  Back to cited text no. 2
    
3.
India – Average Monthly Household Income 2015. Statista N.D. Available from: https://www.statista.com/statistics/653897/average-monthly-household-income-india/. [Last accessed on 2019 Dec 30].  Back to cited text no. 3
    
4.
National Family Health Survey (NFHS-4) 2015-2016 India; 2017.  Back to cited text no. 4
    
5.
Spondyloarthritis in Over 16s: Diagnosis and Management. NICE Guidelines; 2016.  Back to cited text no. 5
    
6.
Selvaraj S, Farooqui HH, Karan A. Quantifying the financial burden of households' out-of-pocket payments on medicines in India: A repeated cross-sectional analysis of National Sample Survey data, 1994-2014. BMJ Open 2018;8:e018020.  Back to cited text no. 6
    
7.
Song IH, Poddubnyy DA, Rudwaleit M, Sieper J. Benefits and risks of ankylosing spondylitis treatment with nonsteroidal antiinflammatory drugs. Arthritis Rheum 2008;58:929-38.  Back to cited text no. 7
    
8.
Gossec L, Dougados M, Phillips C, Hammoudeh M, de Vlam K, Pavelka K, et al. Dissemination and evaluation of the ASAS/EULAR recommendations for the management of ankylosing spondylitis: Results of a study among 1507 rheumatologists. Ann Rheum Dis 2008;67:782-8.  Back to cited text no. 8
    
9.
Maxwell LJ, Zochling J, Boonen A, Singh JA, Veras MM, Tanjong Ghogomu E, et al. TNF-alpha inhibitors for ankylosing spondylitis. Cochrane Database Syst Rev 2015;(4):CD005468.  Back to cited text no. 9
    
10.
Callhoff J, Sieper J, Weiß A, Zink A, Listing J. Efficacy of TNFα blockers in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis: A meta-analysis. Ann Rheum Dis 2015;74:1241-8.  Back to cited text no. 10
    
11.
Baraliakos X, Listing J, Brandt J, Zink A, Alten R, Burmester G, et al. Clinical response to discontinuation of anti-TNF therapy in patients with ankylosing spondylitis after 3 years of continuous treatment with infliximab. Arthritis Res Ther 2005;7:R439-44.  Back to cited text no. 11
    
12.
Chen J, Lin S, Liu C. Sulfasalazine for ankylosing spondylitis. Cochrane Database Syst Rev 2014;(11):CD004800.  Back to cited text no. 12
    
13.
Braun J, Zochling J, Baraliakos X, Alten R, Burmester G, Grasedyck K, et al. Efficacy of sulfasalazine in patients with inflammatory back pain due to undifferentiated spondyloarthritis and early ankylosing spondylitis: A multicentre randomised controlled trial. Ann Rheum Dis 2006;65:1147-53.  Back to cited text no. 13
    
14.
Song IH, Hermann K, Haibel H, Althoff CE, Listing J, Burmester G, et al. Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI (ESTHER): A 48-week randomised controlled trial. Ann Rheum Dis 2011;70:590-6.  Back to cited text no. 14
    
15.
Braun J, van der Horst-Bruinsma IE, Huang F, Burgos-Vargas R, Vlahos B, Koenig AS, et al. Clinical efficacy and safety of etanercept versus sulfasalazine in patients with ankylosing spondylitis: A randomized, double-blind trial. Arthritis Rheum 2011;63:1543-51.  Back to cited text no. 15
    
16.
Khanna Sharma S, Kadiyala V, Naidu G, Dhir V. A randomized controlled trial to study the efficacy of sulfasalazine for axial disease in ankylosing spondylitis. Int J Rheum Dis 2018;21:308-14.  Back to cited text no. 16
    
17.
Damjanov N, Shehhi WA, Huang F, Kotak S, Burgos-Vargas R, Shirazy K, et al. Assessment of clinical efficacy and safety in a randomized double-blind study of etanercept and sulfasalazine in patients with ankylosing spondylitis from Eastern/Central Europe, Latin America, and Asia. Rheumatol Int 2016;36:643-51.  Back to cited text no. 17
    
18.
Fagerli KM, van der Heijde D, Heiberg MS, Wierød A, Kalstad S, Rødevand E, et al. Is there a role for sulphasalazine in axial spondyloarthritis in the era of TNF inhibition? Data from the NOR-DMARD longitudinal observational study. Rheumatology (Oxford) 2014;53:1087-94.  Back to cited text no. 18
    
19.
Vishad VV. A prospective double blind placebo controlled trial of combination disease modifying antirheumatic drugs vs. monotherapy (Sulfasalazine) in patients with inflammatory low backache in ankylosing spondylitis and undifferentiated spondyloarthropathy. J Arthritis 2015;s1:1-6.  Back to cited text no. 19
    
20.
Huang F, Wei JC, Breban M. Thalidomide in ankylosing spondylitis. Clin Exp Rheumatol; 20:S158-61.  Back to cited text no. 20
    
21.
Maugars Y, Mathis C, Berthelot JM, Charlier C, Prost A. Assessment of the efficacy of sacroiliac corticosteroid injections in spondylarthropathies: A double-blind study. Br J Rheumatol 1996;35:767-70.  Back to cited text no. 21
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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