*Most commonly used first-line medication because of the long track record of its application among ocular diseases for over four decades and well-known side effect profile.

Tetracyclines were discovered as the natural fermentation product of the soil bacterium Streptomyces aureofaciens in 1948 and were chemically purified for the first time in 1952 [12]. They have shown efficacy on inflammation, immunomodulation, cell proliferation, angiogenesis, metal chelation, ionophoresis, and bone metabolism [13].

Tetracycline has a direct and indirect anti-inflammatory effect [14, 15]. Tetracycline or minocycline, alone or in combination with nicotinamide, were shown to be effective in cicatricial pemphigoid diseases [16, 17]. Kohler et al., in 1980, showed the synergic anti-neutrophil effect of tetracycline and nicotinamide combination in treatment of erythema elevatum diutinum [18]. Tetracycline (500–2000 mg/day) therapy alone as monotherapy or in combination with nicotinamide (500–2500 mg/day) is also effective in treating pemphigoid [19–21]. Tetracyclines are usually well-tolerated drugs. Common side effects include cutaneous side effects and gastrointestinal upset. Rash, purpura and photosensitivity are reported with both minocycline and doxycycline. Dizziness is reported in almost 10 % of the patients [22].

However, tetracycline’s efficacy to achieve durable remission in OCP has not shown encouraging results. Therefore, the use of tetracycline as monotherapy or in combination with immunosuppressive agents is not administered in the treatment of OCP.

Dapsone is a sulfone derivative (4–4′ diaminodiphenylsulfone) [5] with anti-bacterial and anti-inflammatory properties. In the early twentieth century, theories on selective toxicity based on the ability of certain dyes to kill microbes developed, eventually leading to the discovery of dapsone by Ernest Fourneau and Gladwin Buttle [23]. Dapsone was originally utilized in the treatment of leprosy. Later, in 1953, Rook et al. reported 11 of 17 patients with bullous pemphigoid responded to treatment with sulfapyridine [24]. Person et al. in 1977 and Foster et al. in 1986 confirmed these results, noting the efficacy of dapsone in treating dermatitis herpetiformis and bullous pemphigoid [5, 25].

Dapsone’s applicability in OCP is due to its anti-inflammatory (immunomodulating) effects [26]. The anti-inflammatory mode of action of dapsone is through inhibiting the migration of neutrophilic polymorphonuclear leukocytes [27] and suppressing effects on peroxidase enzyme systems present in monocytes, neutrophils, eosinophils, and mast cells. However, the specific cellular and molecular events involved in the anti-inflammatory effect of dapsone are unknown [5].

Foster et al. studied the efficacy of dapsone in patients with OCP, finding 88 % (14 out of 16) with mild-to-modest inflammatory activity responded to dapsone. Treatment failures in this study were in patients with 3–4+ conjunctival inflammation prior to therapy [5] indicating that dapsone is one drug of choice as first line therapy in mild to moderate OCP [5, 26].

The initial dose of dapsone employed is 2 mg/kg/day with a maximum dose of 200 mg/day. Dosage adjustments are based on therapeutic response and drug tolerance. Patients are monitored every 4–6 weeks; monitoring parameters include CBC emphasized attention on hemoglobin, hematocrit, and reticulocyte count [5].

The most common potential side effects are hemolysis and methaemoglobinemia [5, 27]. Doses greater than 50 mg/day inevitably produce some degree of hemolysis, usually well tolerated [27]. Low-grade hemolysis is acceptable under the circumstances of desired therapeutic response and adequate compensation by reticulocytosis. However, a progressive drop in hematocrit may require discontinuation [5, 26]. Wetheim et al. reported up to 33 % of patients treated with dapsone for OCP with a daily dose of 50 mg twice daily taken orally with clinically significant hemolytic anemia and a persistent fall in hemoglobin from baseline [26]. Previously published reports note approximately 10 % of patients with hemolysis required discontinuation of therapy [5, 28]. Glucose-6-phosphate hydrogenase deficient patients are at a higher risk of developing hemolytic anemia when treated with dapsone [26].

Fern et al. also confirmed dapsone was effective in treating mild to moderate OCP, however, all the patients relapsed after discontinuing therapy [27]. Foster et al. reported 41 % of patients treated with dapsone relapsed within 6 months of discontinuing therapy. Relapsed inflammation responds to either restarting dapsone or starting immunosuppressive agent: azathioprine, 2 mg/kg initial dose [5, 27].

Although dapsone is a relatively safe medication [27], its primary deficiencies are the high rate of recurrence after discontinuation and its inability to control the disease as a monotherapy [5, 27]. Thus, dapsone is not commonly utilized in the treatment of OCP.

In 1948, methotrexate (MTX) was introduced as an anti-neoplastic agent [29]. In 1965, MTX was employed in the treatment of ocular diseases [30], and since then, multiple series have reported its effectiveness in managing ocular inflammation [31–36]. MTX, an anti-metabolite, functions as an immunosuppressive agent through lowering cell proliferation, increasing CD95 sensitivity of activated T-cells leading to an accelerated rate of T-cell apoptosis, inhibiting enzymes involved in purine metabolism and subsequently increasing endogenous adenosine concentrations, and altering cytokine production and humoral responses [37].

Gangaputra et al. retrospectively studied the outcome of noninfectious ocular inflammation when treated with methotrexate as a single, non-corticosteroid immunosuppressive agent. A total of 639 eyes were assessed, affected by multiple etiologies of ocular inflammation and 109 of the included eyes were diagnosed with OCP. Results demonstrated 39.5 % of patients with OCP reached complete suppression of inflammation sustained for ≥28 days within 6 months of treatment. Furthermore, 65 % of the patients with complete control of OCP continued to improve between 6 and 12 months of therapy and reached complete control of inflammation by 12 months of MTX therapy. Corticosteroid-sparing success defined as completely inactive inflammation at ≥2 visits spanning ≥28 days after tapering oral prednisone dose to ≤10 mg/day was observed in 36.5 % of patients with OCP within 6 months of treatment. Moreover, corticosteroid-sparing success continued to improve to 66.9 % within 12 months of treatment. Durable control of inflammation after tapering oral prednisone to ≤5 mg/day was achieved in 60.7 % of patients with OCP [38].

MTX is indicated for mild to moderate OCP; it is administered as one of the first-line medications. Although MTX is available in oral, subcutaneous (SC) and intravenous routes, it is initially employed orally and at once a week dosage, which reduces the potential risk of occult side effects [4, 39]. Patients are observed closely, monitoring CBC, renal panel, and liver function testing every 6 weeks. MTX is initiated at a dose of 15 mg once a week and increased according to the patients’ response and tolerability to treatment, with maximum dose of 40 mg weekly. Folic acid is administered concomitantly at a dose of 1 mg daily.

Patients may develop side effects within the first year of therapy. Gangaputra et al. reported up to 18 % of patients discontinued MTX due to side effects within the first year [38]. The commonly reported side effects are fatigue, GI related: nausea, vomiting and anorexia, and transaminitis [1, 4, 32, 34, 38, 40]. Switching to subcutaneous administration may alleviate gastrointestinal side effect. Other potential side effects include cytopenia, stomatitis [41–44], and pneumonitis [1, 45–48]. Serious and rare adverse effects are bone marrow suppression (0.02 cases/person-year), liver cirrhosis (0.002 cases/person-year), and malignancy [1, 38, 49]. Miserocchi et al. reviewed treatment related side effects in 61 patients with MMP and concluded that MTX exhibited the fewest number of adverse effects, as compared to azathioprine, cyclophosphamide, and dapsone [50]. Baker et al. had similar findings, stating that within the first year of therapy, the portion of patients discontinuing treatment because of side effects was the same among MTX and mycophenolate mofetil (0.09) and significantly higher for azathioprine (0.24) [51]. MTX is a non-dose dependent teratogen, exposure leading to miscarriages and fetal malformations [52, 53]. Therefore, prior to initiating therapy, proper birth control measures should be discussed and recommended, and substitution of therapy should occur ≥3 months before attempting conception [38].

Overall, systemic use of MTX therapy for ocular inflammation is moderately effective in adequately controlling inflammation and decreasing dependency on corticosteroids MTX is tolerated relatively well and carries low risk of serious side effects when patients are closely monitored [38].

In 1957, George Herbert Hitching and Gertrude Elion developed an anti-metabolite medication, azathioprine (Imuran®), which interferes with DNA and RNA synthesis [54], thus acting as an immunosuppressive drug. The first usage of azathioprine was in combination with glucocorticoids to immune suppress post kidney allotransplantation recipients [54–59].

Azathioprine’s first use in the treatment of OCP came after a study by Dantzig in 1974, publishing results of azathioprine in the treatment of OCP [9]. The efficacy of azathioprine in treating OCP was further confirmed by Dave et al., who reported success in the treatment of four patients with mucous membrane pemphigoid with ocular involvement [60]. Currently, azathioprine holds the US Food and Drug Administration approval for the treatment of rheumatoid arthritis [61], organ transplantation [62] and various dermatologic [63], gastrointestinal [64] and rheumatologic diseases [65]. Azathioprine’s pertinence among ophthalmalmic diseases is preventing corneal graft rejections and treating non-infectious ocular inflammatory conditions.

Pasadhika et al. evaluated outcomes of ocular inflammation patients managed on azathioprine as the sole immunosuppressive agent. One hundred forty-five patients were included in the data analysis and of the 145 patients, 33 patients (23 %) had MMP. Each patient was followed from the initiation of azathioprine until therapy was discontinued. Treatment success was evaluated by the time-to-successful tapering of prednisone to ≤10 mg, ≤5 mg, and 0 mg daily while maintaining control of inflammation over at least two visits spanning at least 28 days. Approximately 43 % of MMP patients had control of their ocular inflammation within 6 months of treatment. Corticosteroid-sparing success by 6 months was second highest in MMP (39 %). Patients with intermediate uveitis and mucous membrane pemphigoid (MMP) were most likely to achieve both control of inflammation and corticosteroid-tapering success compared to other ocular inflammatory sites involved in this study [54].

Azathioprine is one of the first-line medications in treating OCP. The recommended dose based on TPMT levels up to 3 mg/kg/day, as the maximum dose [4]. The most common adverse effects leading to discontinuation of azathioprine are gastrointestinal upset, followed by bone marrow suppression, elevated liver enzymes, infection, allergic reaction and arthralgia [4, 54]. Pasadhika et al. estimated 24 % of patients would discontinue azathioprine due to side effects within 1 year [54]. Its main advantages are a lower cost compared to most alternative agents and some evidence of safety during pregnancy [66, 67]_. Also, this medication has been used for ocular inflammatory diseases for the past forty decades, thus unknown long-term toxicities of therapy are less likely [54]. Similar to MTX monitoring, patients are evaluated every 6 weeks, each time with a complete examination and blood work to assess CBC with differential, aspartate transaminase, alanine transaminase, blood urea nitrogen (BUN) and creatinine.

Mycophenolate mofetil (MMF; CellCept®) was originally introduced in the 1950s as an antifungal medication and in the process was discovered to have antineoplastic and immunosuppressive properties [68]. In 1995, the U.S. Food and Drug Administration approved MMF as an immunosuppressive agent to reduce acute renal graft rejection and prolonging renal graft survival [69]. Since then, it has been utilized as a corticosteroid-sparing therapy for solid organ transplant rejection and multiple autoimmune diseases and systemic disorders [70–76]. Ocular application of MMF was first conducted in rats with experimental autoimmune uveitis showing encouraging results [77] and then preliminary studies were performed in humans with OCP [70]. Results revealed MMF to be effective in 9 of 10 eyes (five patients) during 1-year follow-up.

MMF is a morpholinoethyl ester of mycophenolic acid, with an immunosuppressive action by reversible inhibition of inosine-5′ monophosphate dehydrogenase in the de novo pathway of purine synthesis without affecting the salvage pathway of purine synthesis. Therefore, MMF selectively inhibits T- and B- lymphocyte replication [78, 79] and may be the reason for fewer side effects compared to other antimetabolites [75, 78].

Thorne et al. retrospectively evaluated treatment outcomes of MMF in 84 patients with various inflammatory eye diseases, 11 % of these patients were diagnosed with OCP. Treatment success was based on ability to control ocular inflammation and taper oral prednisone to ≤10 mg daily. Treatment success was achieved in 82 % of the patients with median time of 3.5 months with majority of the patients reaching this goal in the first 6 months of treatment. Of the patients to reach treatment success, 70 % were able to taper to ≤5 mg oral prednisone daily successfully, and 40 % were able to discontinue oral prednisone without relapse of their disease. The rate of treatment success among patients who previously had not received IMT was 0.27 per person-month with median time to treatment success of 2.4 months. The rate of treatment success among patients who received IMT previously was 0.09 per person-month with median time to treatment success of 4.7 months. Even then, treatment success was >60 % among patients previously treated with IMT. In conclusion, MMF is not only an effective corticosteroid-sparing agent to treat OCP but also among patients resistant to other IMTs [80].

Doycheva et al. were the first to report long-term efficacy and tolerability of MMF in the therapy of OCP. The study consisted of retrospectively assessing 19 eyes with OCP diagnosis that were treated with MMF with follow-up of at least 4 years. At the time of MMF treatment initiation, 17 of 19 eyes (89 %) had active inflammation. During the therapy, 11 eyes (58 %) had complete resolution of inflammation and 8 eyes (11 %) had mild inflammation. Rate of relapse was 0.09 per patient-year with a mean time of 42 months after the initiation of MMP. Also during treatment, progression of conjunctival cicatrization was prevented in 9 eyes (47 %), mild progression of cicatrization was reported in 8 eyes (42 %) and conjunctival cicatrization progressed to stage IV in 2 eyes (11 %). Overall, the results from this study suggest MMF is an adequate immunosuppressive agent with the capacity to maintain long-term inflammatory control and recommending it as first-line therapy for patients with OCP [81].

Nottage et al. retrospectively studied the outcomes of inflammatory control and rate of discontinuation of MMF in the treatment of OCP. The study consisted of 23 OCP patients that were treated with MMF. All of the patients had disease process of Foster stage 2 or greater. Eight out of the 23 patients (34.8 %) had failed IMT previously. Fifteen of the 23 patients (65.2 %) were treated with MMF as initial therapy. Overall, 19 patients achieved control of inflammation, and 16 out of the 19 patients (82.4 %) were treated with MMF as monotherapy. Of all the patients who achieved inflammatory suppression (19 patients), 3.27 months was the median length of time to disease control. The patients who had failed IMT previously, 4.10 months was the median length of time to disease control and 3.85 months for those who were IMT naïve prior to starting MMF. In 5 of the total 23 patients, MMF was discontinued due to response failure (4 patients) and allergic reaction (1 patient). Based on these observations, MMF was concluded to be an appropriate monotherapy and initial systemic immunosuppressive agent for controlling active OCP [82].

Side effect profile of MMF is found to be minimal and overall well tolerated [68, 70, 80, 83–86]. Nottage et al. observed 3 out of 23 patients to have developed side effects. One of the three patients (4.3 %) developed a rash leading to cessation of MMF. Another patient had mild thrombocytopenia, which resolved with a decrease in MMF dose. Third patient had hypokalemia, myalgia, insomnia, and anorexia, which also resolved with lowering the dose and switching to mycophenolate sodium [82]. Saw et al. and Doycheva et al. both reported mild and transient side effects of MMF while evaluating the effectiveness and toxicity of different IMT in OCP management [81, 84]. Saw et al. went on to conclude MMF having the lowest risk of side effects when compared to other IMT [84]. The most common potential side effects observed with the use of MMF are gastrointestinal upset (diarrhea, vomiting), increased liver enzymes, and fatigue [68, 71, 80, 81] which are typically reversible and resolve with dose reduction. MMF has not been associated with causing any major organ toxicity, infection or malignancy [71, 81, 82].

MMF is employed as an orally administered medication, initially at a dose of 500 mg twice a day and titrated depending on disease control and tolerability with a maximum dose of 3 g/day. Similar to other IMT monitoring, patients are evaluated every 6 weeks and blood work is obtained to assess CBC with differential, renal panel, and liver function testing. The most appropriate application of MMF is to utilize it as a corticosteroid-sparing, first-line, monotherapy or as an adjunctive immunosuppressive agent for active OCP [68, 70, 80–82, 87].

Cyclophosphamide (Cytoxan®), a nitrogen mustard derived alkylating agent, became the eighth cytotoxic anticancer medication to be approved by the United States Food and Drug Administration [88, 89]. The first use of cyclophosphamide in ocular conditions was in 1952 to treat idiopathic uveitis [90] and since then it has been used to treat various ocular inflammatory diseases [91, 92]. Cyclophosphamide generates immunomodulatory effects on rapidly proliferating cells, by alkylating nucleophilic groups on DNA bases leading to cross-linking of DNA bases, abnormal base pairing, or DNA strand breakage. The end result is damage to cells undergoing mitosis and consequently suppression of lymphocyte function (B cells more than T cells) [1, 92, 93].

Pujari et al. assessed the outcomes of cyclophosphamide therapy as a single immunosuppressive agent during follow-up, with or without local or systemic corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs), for treating non-infectious ocular inflammation. Of the 215 patients in this study, 45.6 % had OCP, being the most common diagnosis in affected eyes. Results revealed that within 6 months, 43 % of patients with OCP had complete control of inflammation, sustained over at least two visits spanning at least 28 days. Success continued to improve, complete inactivity was observed in 68.7 % patients with OCP by 12 months. Disease remission leading to discontinuation of the medication occurred at the rate of 0.32/person-year and 63.1 % of patients achieved remission at or prior to 2 years [92]. Overall, cyclophosphamide achieved beneficial effects with sustained control of inflammation among non-infectious ocular inflammatory cases in 49 and 76 % by 6 and 12 months respectively [92].

Elder et al. conducted a prospective study among 19 eyes of ten patients diagnosed with either severe OCP or marked OCP who previously failed other systemic immunosuppressive therapy. They were treated with cyclophosphamide and short-term high dose oral prednisolone. All patients were treated with oral cyclophosphamide at an initial dose of 1.5–2.0 mg/kg/day and oral prednisolone 60 mg/day or 80 mg/day and other oral immunosuppressive agents were discontinued. All but one patient were treated with cyclophosphamide for longer than 6 months. The reason for discontinuing treatment in one patient was due to unpleasant feelings of being distant from the world, ‘like being on [recreational] drugs’. The goal lymphocyte count was 0.5–1.0 × 10⁹/l, which was accomplished on a maintenance dose ranging from 50 to 150 mg/day. When clinical response was observed, prednisolone was reduced and when ocular and systemic features were clinically stable, prednisolone was stopped completely. The duration of prednisolone ranged from 4 to 8 months. The results of this study revealed ocular inflammation resolved in 15 eyes in a mean time of 2.4 months. During this study two eyes perforated; one from acute microbial keratitis and the other from progressive corneal thinning. Throughout the study, systemic infections requiring antibiotics did not develop in any of the patients. Progressive cicatrization was observed in 21 % of inflamed eyes (4 out of 19 eyes). Overall, these results suggest cyclophosphamide plus short term high dose oral prednisolone effectively controls severe ocular inflammation seen in OCP, although progression of ocular cicatrization might be inevitable in some cases [89]. Mondino et al. [10, 94] and Foster et al. [5, 95] reported findings confirming Elder et al.’s work, describing oral cyclophosphamide and short-term high dose prednisolone to be the most reasonable therapeutic regimen for adequate control of ocular inflammation and prevention of cicatrization among OCP patients.

Intravenously (IV) administered cyclophosphamide is used for rapid ocular inflammatory arrest, specifically prior to ocular surface surgery. High dose oral prednisone is also initiated simultaneously; dosed 1 mg/kg/day with a maximum dose of 60 mg/day and tapered weekly. Inflammation that has failed to respond to less potent immunomodulatory therapy is also treated with pulse IV cyclophosphamide therapy [96, 97]. IV cyclophosphamide is dosed at 1 g/m² body surface area every 2 weeks. The dose is adjusted depending on the patients’ response and tolerability to treatment, and white blood count (WBC) with an optimal range of 3.0 ×10³/μL to 4.5 ×10³/μL. Oral dosing given in 100–150 mg/day range (“full” doses) appear more likely to succeed (controlling inflammation compared to doses of <100 mg but more likely to lead to dose-limiting toxicity) than lower doses [92]. Good hydration is encouraged, 8–10 cups of non-caffeinated fluid daily to prevent bladder toxicity especially with oral cyclophosphamide and hydration is supplemented with infusions for IV cyclophosphamide [91].

Careful consideration is exercised before starting cyclophosphamide; it is reserved for vision-threatening ocular diseases which have previously failed less potent immunomodulatory therapy or non-infectious ocular inflammatory cases associated with systemic disease. After treatment with cyclophosphamide, a higher rate of medication-free remission has been reported compared to methotrexate [38], azathioprine [54], mycophenolate mofetil [83] and cyclosporine [98]. However, given the side effect profile of the medication, diligent monitoring by an ophthalmologist and commitment to compliance by the patient are fundamental to achieve optimal results.

Pujari et al. found that the most common side effects leading to discontinuation of cyclophosphamide are leukopenia and cystitis/blood in the urine, seen in 18.1 and 7.7 % respectively within the first year of therapy. The most common opportunistic infection leading to discontinuation is Pneumocystis carinii, reported in 3.0 % of the patients in the first year [92]. Cyclophosphamide increases the risk of malignancy, especially bladder carcinoma [9, 89, 99] and increases overall cancer mortality [49, 100–103]. Therefore, the use of cylcophosphamide is limited to 1 year due to the increased risk of developing cancer [91]. Also, it crosses the placental blood barrier and is excreted in breast milk, thus is classified as a teratogenic medication and contraindicated if a patient is breastfeeding [104, 105]. Although the potential side effects of cyclophosphamide are greater than alternative immunosuppressive agents, its application should not be deferred or delayed under appropriate circumstances when this medication is indicated given its success rates of remission and vision-saving capacity [92].

Close monitoring is especially emphasized with the use of cyclophosphamide. CBC with differential is required every other week for IV cyclophosphamide to ensure the WBC is within the optimal range. For both IV and oral cyclophosphamide, monitoring CBC, renal panel, liver function enzymes, and urine analysis every 6 weeks is endorsed. Being that cyclophosphamide is recommended to be employed for no longer than 1 year, patients are transitioned to other IMT (i.e., MTX, azathioprine, mycophenolate) to achieve 2 full years of corticosteroid-free remission.

Plasmapheresis refers to extracorporeal separation of blood components resulting in filtered plasma. Methods used in plasmapheresis to achieve filtered plasma are centrifugation, double filtration plasmapheresis (DFPF) and a combination of both techniques [106, 107]. It has been proven to be effective in the variety of the diseases, especially in those in which circulating antibodies are the main pathogenesis factor. Clinical indications are broad and include more than 60 diseases [108]. Although there is no formal recommendation in using plasmapheresis in treatment of bolus pemphigoid, several reports advocated its beneficial application in conjunction with immunosuppressive therapy in controlling severe or refractory cases, specifically with persistent ocular involvement [109–112].